Fogli A

Gert C. Scheper

Kaczorowska M

Lara Brandão

Leegwater PAJ

Lucia Maria da Costa Fontenelle

Marjo S. van der Knaap

Prass K

Ramaswamy V

Rosemberg S

Schiffmann R

van der Knaap MS

Vermeulen G

Wu Y

Fontenelle, L.M. da Costa

Scheper, G.C.

Brandao, L.

Knaap, M.S. van der

DSpace at VU

Arq Neuropsiquiatr 2008;66(3-A):549-551
 549
Clinical / Scientific note
ATYPICAL PRESENTATION Of VANISHING 
WHITE MATTER DISEASE
Lucia Maria da Costa Fontenelle1, Gert C. Scheper2, Lara Brandão3, Marjo S. van der Knaap2
ATAXIA DA INfÂNCIA COM HIPOMIELINIZAÇÃO CENTRAL ATíPICA
1Neuropediatra do Instituto de Puericultura e Pediatria Martagão Gesteira da Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ, Brazil; 2University 
Medical Center Amsterdan, The Netherlands; 3Médica radiologista do Serviço de Ressonância Magnética Fellipe Mattoso, Rio de Janeiro RJ, Brazil.
Received 29 February 2008, received in final form 13 May 2008. Accepted 10 June 2008.
Dra. Lucia Maria da Costa Fontenelle – Rua Sorocaba 464 / 302 - 22271-110 Rio de Janeiro RJ - Brasil. E-mail: luciafontenelle@hotmail.com
Leukoencephalopathy with vanishing white matter 
(VWM) has also been called childhood ataxia with cen-
tral hypomyelination (CACH)1. VWM was described by van 
der Knaap et al.2 in nine children with a leukoencephalop-
athy of similar type according to clinical and MRI find-
ings. The onset of the disease was in childhood and the 
disease course was chronic-progressive with additional 
episodes of rapid deterioration. The MRI showed diffuse 
and bilateral leukoencephalopathy with areas that dis-
played a signal intensity close to that of cerebrospinal flu-
id (CSF) on different pulse sequences. As the disease pro-
gressed white matter rarefaction and cystic degeneration 
increased. VWM is a disease with an autosomal recessive 
mode of inheritance. It is related to defects in translation 
initiation factor eIF2B3,4. eIF2B consists of 5 non identical 
subunits. Clinically the disease is characterized mainly by 
cerebellar ataxia, usually less prominent spasticity, rela-
tively mild mental decline, and no or mild epilepsy. Op-
tic atrophy may develop, but is not obligatory2. Episodes 
of minor head trauma, febrile infections or fright can re-
sult in worsening of the symptoms with subsequent par-
tial recovery2,4-7. The deterioration is often accompanied 
by lethargy and may result in unexplained coma2. Most 
patients die after 2–5 years of disease evolution5. Nowa-
days, it is known that the diagnostics based on the clinical 
aspects is not always easy. The onset of the disease can 
be at any age, from antenatal to adult onset2,5,8-11. The evo-
lution may be rapid or prolonged3. Death may occur soon 
or after decades5,8. Other organs than the nervous system 
may be affected, especially in early onset8,12. There may be 
unexpected neurological manifestations such as period-
ic hemiparesis13. Beside the different phenotypes, another 
situation that could lead to a mistake or delay in the diag-
nosis is the dissociation between the clinical findings and 
MR images on which the abnormality of the white matter 
may appear before the clinical phenomena2.
So VWM is a disease that presents with different phe-
notypes and the diagnosis is not always easy. With more 
universal access to the MRI, the diagnosis should be con-
sidered more often. The diagnosis is confirmed by genet-
ic testing, which allows a better definition of the clinical 
profile of this disease. 
CASE
A boy, 8 years and 10 months old, felt dizziness in June 2006. 
CT scan revealed bilateral and diffuse brain hypodensity. Soon 
after, a MRI was performed suggesting a leukodystrophy. He was 
sent for neurological investigation and was seen on the 31st of 
Agust, 2006. At that time, he had no complaints. 
The pregnancy was complicated due to a disease in his 
mother (kidney tumor). A caesarean section was performed at 
term and the baby was healthy. There was a normal psychomo-
tor development and satisfactory progress at school with nor-
mal behavior. He had a good general health. He had an older sis-
ter, who was healthy. There was no consanguinity in the family. 
There was a case of epilepsy in an uncle. The neurological exam 
was entirely normal at that time.
Laboratory exams ruled out X-linked adrenoleukodystrophy 
and metachromatic leukodystrophy. Chromatography of amino 
acids in the blood and urine, among other results, did not clarify 
the diagnosis. The MRI with spectroscopy was repeated in 2006 
and showed alterations suggesting VWM (Fig 1). A new MRI in Ju-
ly 2007 was unchanged (Fig 2).
Genetic analysis showed that the patient was compound 
heterozygous for two mutations in EIF2B5: 1) p.Arg113His, also 
present in father, and 2) p.Met608lle, also present in the moth-
er. These findings confirmed the diagnosis of VWM, as suggest-
ed by the MRI findings. 
One year and half after the diagnosis the patient is still 
without symptoms and the neurological exam continues to be 
normal. 
Arq Neuropsiquiatr 2008;66(3-A)
550
Vanishing white matter disease
Fontenelle et al.
DISCUSSION
Pre-symptomatic cases have already been observed by 
many authors. van der Knaap et al. describe two of these 
cases in 1997 and one case in 199811. In the article of 1998, 
5 patients were analyzed who had a later onset of the dis-
ease; one of them had a normal life at the age of 22, but he 
was always clumsy in his motor activities and he also had 
learning difficulties. His neurological exam revealed, at the 
age of 22, minor cerebellar ataxia and brisk tendon reflex-
es of the legs. The MRI, made at the age of 21, presented 
typical image of VWM but with a milder degree of white 
matter involvement than observed in more serious cases. 
Except for one of the 5 patients, who died at the age of 
16, the others were alive after the age of 20 years. All the 
patients, in that time, had motor signs. Wu and colleagues14 
described 1 case – among 9 patients – without clinical signs 
and with typical alterations on MRI. However, in all 9 pa-
tients the onset of the disease occurred between 6 months 
and 3 years of age and the deterioration was observed in 
all cases, after respiratory infection in 6 cases and light 
brain trauma in 3. A Brazilian paper, from Rosemberg et 
al.15, has also mentioned the alterations of the white mat-
ter that preceded the clinical symptoms in 2 of the 4 cases. 
In both cases the onset was between 8 and 34 months of 
age and characterized by cerebellar ataxia and spasticity.
The case of our patient does not fit entirely in the 
ones reported before. He was almost 9 years old when his 
complaint of feeling dizzy occurred. It lasted a few days 
and disappeared without treatment. Such symptom is not 
usually associated with the onset of VWM. The complaint 
was not preceded by fever, trauma or any other kind of 
stress. The neurological exam did not demonstrate abnor-
mality in any period and no motor deterioration was seen 
after 18 months. The MRI has also remained unchanged. 
The diagnosis would certainly not have been made if the 
patient would not have had an MRI, which in most cases 
is not requested for isolated dizziness.
Fogli and Boespflug-Tanguy5 described 148 cases of 
VWM and demonstrated how important it is to pay at-
tention to the diversity of clinical manifestations found 
in each case. A wide clinical spectrum has been observed 
in these patients, from congenital forms with rapid death 
to adult-onset forms with slow mental decline and pro-
gressive motor dysfunction, sometimes associated with 
congenital eye abnormalities or ovariodysgenesis. van der 
Knaap, Pronk and Scheper10 agree with the wide pheno-
typic variability of VWM and they report that there is 
some genotype-phenotype correlation in VWM patients. 
Some mutations are consistently, although not invariably, 
associated with a mild phenotype whereas others muta-
tions are consistently associated with a severe phenotype. 
But, the authors report that there is much variation be-
tween patients carrying the same mutations and between 
affected siblings in the same family. Consequently, envi-
ronmental and other genetic factors influence the phe-
notype as well. The impression obtained from the litera-
ture studied and from the experience with our patient, 
whose diagnosis was unexpected, is that with MRI becom-
ing more widely available more cases will be found with 
other unusual presentation. 
Fig 1. MRI 2006. White matter with signal intensity similar to the ce-
rebrospinal fluid (arrow).
Fig 2. MRI 2007. Similar appearance to the preceding MRI.
Arq Neuropsiquiatr 2008;66(3-A)
 551
Vanishing white matter disease
Fontenelle et al.
Acknowledgment – The authors are grateful to Fleury Labora-
tory that has made the transport of the blood from the patient and 
his family to the lab in The Netherlands, and to Dr Fernando Kock 
and Dra Renata Gomes Nunes who were interested in such proceed-
ing and made this event possible. 
REfERENCES
  1. Schiffmann R, Moller JR, Trapp BD, et al. Childhood ataxia with diffuse 
central nervous system hypomyelination. Ann Neurol 1994;36:932-933.
  2. van der Knaap MS, Barth PG, Gabreels, et al. A new leukoencephalpha-
thy with vanishing white matter. Neurology 1997;48:845-855.
 3.  Leegwater PAJ, Vermeulen G, Könst AAM, van der Knaap MS. Sub-
units of the translation factor eIF2B are mutant in leukoencephalopa-
thy with vanishing white matter. Nature Genetics 2001;29:383-388.
 4.  van der Knaap MS, Leegwater PA, Könst AA, et al. Mutations in each of 
the five subunits of translation initiation factor eIF2B can cause leukoen-
cephalopathy with vanishing white matter. Ann Neurol 2002;51:264-270.
 5.  Fogli A, Boespflug-Tanguy O. The large spectrum of eIF2B-related dis-
eases. Biochem Soc Trans 2006;34:22-29.
 6.  Vermeulen G, Seild R, Mercimek-Mahmutoglu S, Rotteveel JJ, Scheper 
GC, van der Knaap MS. Frigth is a provoking factor in vanishing white 
matter disease. Ann Neurol, 2005;57:560-563.
 7.  Kaczorowska M, Kuczynski D, Jurkieeicz E, Scheper GC, van der Knaap 
MS, Jozwiak S. Acute frigth induces onset of symptoms in vanishing 
white matter disease: case report. Eur J Paediatr Neurol, 2006;10:192-193.
 8.  van der Knaap MS, van Berkel CGM, Herms J, et al. eIF2B-related dis-
orders: antenatal onset and involvement of multiple organs. Am J Hum 
Genet 2003;73:1199-1207.
 9.  Prass K, Bruck W, Schroder NW, et al. Adult-onset leukoencephalopha-
thy with vanishing white matter presenting with dementia. Ann Neu-
rol 2001;50:665-668.
10. van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter dis-
ease. Lancet Neurol 2006;5:413-423.
11.  van der Knaap MS, Kamphorst W, Barth PG,. Kraaijeveld CL, Gut E, 
Valk J. Phenotypic variation in leucoencephalopathy with vanishing 
white matter. Neurology 1998;51:540-547.
12.  Schiffmann R, Elroy-Stein O. Childhood ataxy with CNS hypomielin-
ation/vanishing white matter disease: a common leukodystrophy 
caused by abnormal control of protein synthesis. Mol Genet Metab 
2006;88:7-15.
13.  Ramaswamy V, Chan AK, Kolski HK. Vanishing white matter disease 
with periodic (paroxysmal) hemiparesis. Pediatr Neurol 2006;35:65-68.
14.  Wu Y, Jiang YW, Qin J, et al. Clinical characteristics of cases with leu-
koencephalophathy with vanishing white. Zhonghua Er Ke Za Zhi 
2007;45:115-120.
15.  Rosemberg S, Leite CC, Arita FN, Kliemann SE, Lacerda MT. Leukoen-
cephalopathy with vanishing white matter disease: report of four cases 
from three unrelated Brazilian families. Brain Dev 2002; 24:250-256.


Atypical presentation of vanishing white matter disease

da Costa Fontenelle, L.M.

van der Knaap, M.S.

VU Research Portal

VU Research PortalAtypical presentation of vanishing white matter diseaseda Costa Fontenelle, L.M.; Scheper, G.C.; Brandao, L.; van der Knaap, M.S.published inArquivos de neuro-psiquiatria2008DOI (link to publisher)10.1590/S0004-282X2008000400022document versionPublisher's PDF, also known as Version of recordLink to publication in VU Research Portalcitation for published version (APA)da Costa Fontenelle, L. M., Scheper, G. C., Brandao, L., & van der Knaap, M. S. (2008). Atypical presentation ofvanishing white matter disease. Arquivos de neuro-psiquiatria, 66(3A), 549-551. https://doi.org/10.1590/S0004-282X2008000400022General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.E-mail address:vuresearchportal.ub@vu.nlDownload date: 26. May. 2021Arq Neuropsiquiatr 2008;66(3-A):549-551 549Clinical / Scientific noteATYPICAL PRESENTATION Of VANISHING WHITE MATTER DISEASELucia Maria da Costa Fontenelle1, Gert C. Scheper2, Lara Brandão3, Marjo S. van der Knaap2ATAXIA DA INfÂNCIA COM HIPOMIELINIZAÇÃO CENTRAL ATíPICA1Neuropediatra do Instituto de Puericultura e Pediatria Martagão Gesteira da Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ, Brazil; 2University Medical Center Amsterdan, The Netherlands; 3Médica radiologista do Serviço de Ressonância Magnética Fellipe Mattoso, Rio de Janeiro RJ, Brazil.Received 29 February 2008, received in final form 13 May 2008. Accepted 10 June 2008.Dra. Lucia Maria da Costa Fontenelle – Rua Sorocaba 464 / 302 - 22271-110 Rio de Janeiro RJ - Brasil. E-mail: luciafontenelle@hotmail.comLeukoencephalopathy with vanishing white matter (VWM) has also been called childhood ataxia with cen-tral hypomyelination (CACH)1. VWM was described by van der Knaap et al.2 in nine children with a leukoencephalop-athy of similar type according to clinical and MRI find-ings. The onset of the disease was in childhood and the disease course was chronic-progressive with additional episodes of rapid deterioration. The MRI showed diffuse and bilateral leukoencephalopathy with areas that dis-played a signal intensity close to that of cerebrospinal flu-id (CSF) on different pulse sequences. As the disease pro-gressed white matter rarefaction and cystic degeneration increased. VWM is a disease with an autosomal recessive mode of inheritance. It is related to defects in translation initiation factor eIF2B3,4. eIF2B consists of 5 non identical subunits. Clinically the disease is characterized mainly by cerebellar ataxia, usually less prominent spasticity, rela-tively mild mental decline, and no or mild epilepsy. Op-tic atrophy may develop, but is not obligatory2. Episodes of minor head trauma, febrile infections or fright can re-sult in worsening of the symptoms with subsequent par-tial recovery2,4-7. The deterioration is often accompanied by lethargy and may result in unexplained coma2. Most patients die after 2–5 years of disease evolution5. Nowa-days, it is known that the diagnostics based on the clinical aspects is not always easy. The onset of the disease can be at any age, from antenatal to adult onset2,5,8-11. The evo-lution may be rapid or prolonged3. Death may occur soon or after decades5,8. Other organs than the nervous system may be affected, especially in early onset8,12. There may be unexpected neurological manifestations such as period-ic hemiparesis13. Beside the different phenotypes, another situation that could lead to a mistake or delay in the diag-nosis is the dissociation between the clinical findings and MR images on which the abnormality of the white matter may appear before the clinical phenomena2.So VWM is a disease that presents with different phe-notypes and the diagnosis is not always easy. With more universal access to the MRI, the diagnosis should be con-sidered more often. The diagnosis is confirmed by genet-ic testing, which allows a better definition of the clinical profile of this disease. CASEA boy, 8 years and 10 months old, felt dizziness in June 2006. CT scan revealed bilateral and diffuse brain hypodensity. Soon after, a MRI was performed suggesting a leukodystrophy. He was sent for neurological investigation and was seen on the 31st of Agust, 2006. At that time, he had no complaints. The pregnancy was complicated due to a disease in his mother (kidney tumor). A caesarean section was performed at term and the baby was healthy. There was a normal psychomo-tor development and satisfactory progress at school with nor-mal behavior. He had a good general health. He had an older sis-ter, who was healthy. There was no consanguinity in the family. There was a case of epilepsy in an uncle. The neurological exam was entirely normal at that time.Laboratory exams ruled out X-linked adrenoleukodystrophy and metachromatic leukodystrophy. Chromatography of amino acids in the blood and urine, among other results, did not clarify the diagnosis. The MRI with spectroscopy was repeated in 2006 and showed alterations suggesting VWM (Fig 1). A new MRI in Ju-ly 2007 was unchanged (Fig 2).Genetic analysis showed that the patient was compound heterozygous for two mutations in EIF2B5: 1) p.Arg113His, also present in father, and 2) p.Met608lle, also present in the moth-er. These findings confirmed the diagnosis of VWM, as suggest-ed by the MRI findings. One year and half after the diagnosis the patient is still without symptoms and the neurological exam continues to be normal. Arq Neuropsiquiatr 2008;66(3-A)550Vanishing white matter diseaseFontenelle et al.DISCUSSIONPre-symptomatic cases have already been observed by many authors. van der Knaap et al. describe two of these cases in 1997 and one case in 199811. In the article of 1998, 5 patients were analyzed who had a later onset of the dis-ease; one of them had a normal life at the age of 22, but he was always clumsy in his motor activities and he also had learning difficulties. His neurological exam revealed, at the age of 22, minor cerebellar ataxia and brisk tendon reflex-es of the legs. The MRI, made at the age of 21, presented typical image of VWM but with a milder degree of white matter involvement than observed in more serious cases. Except for one of the 5 patients, who died at the age of 16, the others were alive after the age of 20 years. All the patients, in that time, had motor signs. Wu and colleagues14 described 1 case – among 9 patients – without clinical signs and with typical alterations on MRI. However, in all 9 pa-tients the onset of the disease occurred between 6 months and 3 years of age and the deterioration was observed in all cases, after respiratory infection in 6 cases and light brain trauma in 3. A Brazilian paper, from Rosemberg et al.15, has also mentioned the alterations of the white mat-ter that preceded the clinical symptoms in 2 of the 4 cases. In both cases the onset was between 8 and 34 months of age and characterized by cerebellar ataxia and spasticity.The case of our patient does not fit entirely in the ones reported before. He was almost 9 years old when his complaint of feeling dizzy occurred. It lasted a few days and disappeared without treatment. Such symptom is not usually associated with the onset of VWM. The complaint was not preceded by fever, trauma or any other kind of stress. The neurological exam did not demonstrate abnor-mality in any period and no motor deterioration was seen after 18 months. The MRI has also remained unchanged. The diagnosis would certainly not have been made if the patient would not have had an MRI, which in most cases is not requested for isolated dizziness.Fogli and Boespflug-Tanguy5 described 148 cases of VWM and demonstrated how important it is to pay at-tention to the diversity of clinical manifestations found in each case. A wide clinical spectrum has been observed in these patients, from congenital forms with rapid death to adult-onset forms with slow mental decline and pro-gressive motor dysfunction, sometimes associated with congenital eye abnormalities or ovariodysgenesis. van der Knaap, Pronk and Scheper10 agree with the wide pheno-typic variability of VWM and they report that there is some genotype-phenotype correlation in VWM patients. Some mutations are consistently, although not invariably, associated with a mild phenotype whereas others muta-tions are consistently associated with a severe phenotype. But, the authors report that there is much variation be-tween patients carrying the same mutations and between affected siblings in the same family. Consequently, envi-ronmental and other genetic factors influence the phe-notype as well. The impression obtained from the litera-ture studied and from the experience with our patient, whose diagnosis was unexpected, is that with MRI becom-ing more widely available more cases will be found with other unusual presentation. Fig 1. MRI 2006. White matter with signal intensity similar to the ce-rebrospinal fluid (arrow).Fig 2. MRI 2007. Similar appearance to the preceding MRI.Arq Neuropsiquiatr 2008;66(3-A) 551Vanishing white matter diseaseFontenelle et al.Acknowledgment – The authors are grateful to Fleury Labora-tory that has made the transport of the blood from the patient and his family to the lab in The Netherlands, and to Dr Fernando Kock and Dra Renata Gomes Nunes who were interested in such proceed-ing and made this event possible. REfERENCES  1. Schiffmann R, Moller JR, Trapp BD, et al. Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol 1994;36:932-933.  2. van der Knaap MS, Barth PG, Gabreels, et al. A new leukoencephalpha-thy with vanishing white matter. Neurology 1997;48:845-855. 3.  Leegwater PAJ, Vermeulen G, Könst AAM, van der Knaap MS. Sub-units of the translation factor eIF2B are mutant in leukoencephalopa-thy with vanishing white matter. Nature Genetics 2001;29:383-388. 4.  van der Knaap MS, Leegwater PA, Könst AA, et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoen-cephalopathy with vanishing white matter. Ann Neurol 2002;51:264-270. 5.  Fogli A, Boespflug-Tanguy O. The large spectrum of eIF2B-related dis-eases. Biochem Soc Trans 2006;34:22-29. 6.  Vermeulen G, Seild R, Mercimek-Mahmutoglu S, Rotteveel JJ, Scheper GC, van der Knaap MS. Frigth is a provoking factor in vanishing white matter disease. Ann Neurol, 2005;57:560-563. 7.  Kaczorowska M, Kuczynski D, Jurkieeicz E, Scheper GC, van der Knaap MS, Jozwiak S. Acute frigth induces onset of symptoms in vanishing white matter disease: case report. Eur J Paediatr Neurol, 2006;10:192-193. 8.  van der Knaap MS, van Berkel CGM, Herms J, et al. eIF2B-related dis-orders: antenatal onset and involvement of multiple organs. Am J Hum Genet 2003;73:1199-1207. 9.  Prass K, Bruck W, Schroder NW, et al. Adult-onset leukoencephalopha-thy with vanishing white matter presenting with dementia. Ann Neu-rol 2001;50:665-668.10. van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter dis-ease. Lancet Neurol 2006;5:413-423.11.  van der Knaap MS, Kamphorst W, Barth PG,. Kraaijeveld CL, Gut E, Valk J. Phenotypic variation in leucoencephalopathy with vanishing white matter. Neurology 1998;51:540-547.12.  Schiffmann R, Elroy-Stein O. Childhood ataxy with CNS hypomielin-ation/vanishing white matter disease: a common leukodystrophy caused by abnormal control of protein synthesis. Mol Genet Metab 2006;88:7-15.13.  Ramaswamy V, Chan AK, Kolski HK. Vanishing white matter disease with periodic (paroxysmal) hemiparesis. Pediatr Neurol 2006;35:65-68.14.  Wu Y, Jiang YW, Qin J, et al. Clinical characteristics of cases with leu-koencephalophathy with vanishing white. Zhonghua Er Ke Za Zhi 2007;45:115-120.15.  Rosemberg S, Leite CC, Arita FN, Kliemann SE, Lacerda MT. Leukoen-cephalopathy with vanishing white matter disease: report of four cases from three unrelated Brazilian families. Brain Dev 2002; 24:250-256.

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