Genetic variations and humoral immune responses to myelin
oligodendroglia glycoprotein in adult phenotypes of
X-linked adrenoleukodystrophy
Stephan Schmidta,*, Giovanna Maria Marrosub, Heike Kolschc, Claus G. Haased,Stanislav Ferenczike, Piotr Sokolowskif, Wolfgang Kohlerf, Martina Schmidta,
Andreas Papassotiropoulosg, Reinhard Heunc, Hans Grosse-Wildee, Thomas Klockgethera
aDepartment of Neurology, University of Bonn, Sigmund-Freud-Str. 20, 53105 Bonn, GermanybMultiple Sclerosis Center, University of Cagliari, Cagliari, Italy
cDepartment of Psychiatry and Psychotherapy, University of Bonn, Bonn, GermanydDepartment of Neurology, University of Essen, Essen, Germanye Institute of Immunology, University of Essen, Essen, Germany
fNeurological Department of Sachsisches Krankenhaus, Wermsdorf, GermanygDepartment of Psychiatry, University of Zurich, Zurich, Switzerland
Received 28 August 2002; received in revised form 15 November 2002; accepted 3 December 2002
Abstract
The lack of phenotype/genotype association in X-linked adrenoleukodystrophy (X-ALD) has prompted the search for disease modifying
factors. We previously demonstrated increased serum antibody responses against myelin oligodendrocyte glycoprotein (MOG) in various
clinical phenotypes of X-ALD allowing speculations that myelin specific humoral immune responses might be involved in phenotype
generation of X-ALD. In the present study, we investigated the possible association of (1) a naturally occurring variable number tandem
repeat (vntr) polymorphism (C allele) in the 3V flanking region of the interleukin-6 gene (IL-6), previously demonstrated to modify the course
of Alzheimer’s disease, systemic lupus erythematodes and Multiple Sclerosis (MS), (2) a tetranucleotide repeat polymorphism (TAAA)n in
the 3V flanking region of the MOG gene and (3) HLA class II alleles with adult clinical phenotypes and serum antibody responses to MOG in
70 adult X-ALD patients. HLA class II alleles, (TAAA)n MOG gene polymorphisms, and IL-6 C allele were not associated with clinical
phenotypes. Anti-MOG antibodies were detectable in 17/54 X-ALD patients (31.5%). Anti-MOG antibodies were associated with the 226 bp
(TAAA)n MOG gene polymorphism but not with distinct clinical phenotypes.
D 2002 Elsevier Science B.V. All rights reserved.
Keywords: Adrenoleukodystrophy; Adrenomyeloneuropathy; Myelin oligodendrocyte glycoprotein; HLA; Interleukin-6
1. Introduction
X-linked adrenoleukodystrophy (X-ALD) is an inherited
disorder of peroxisomal metabolism characterized by the
accumulation of very long chain fatty acids (VLCFA) in the
nervous system, the adrenal glands and testes (Moser, 1997).
Following the cloning of the X-ALD gene, more than 300
mostly ‘‘kindred-specific’’ mutations have been identified
(Moser, 1997). Notably, there is virtually no correlation
between different kinds of mutations and a particular clinical
phenotype, not even within the same kindred. Most strik-
ingly, the two most common phenotypes, cerebral ALD
(CALD) and adrenomyeloneuropathy (AMN), are not only
distinct with regard to the age of onset (CALD predom-
inantly in childhood, AMN almost exclusively in adulthood)
but also with regard to the pattern of nervous system
involvement (confluent cerebral inflammatory demyelinat-
ing lesions in CALD, neuronopathy of long tracts in the
myelon in association with a peripheral neuropathy with
little or no signs of inflammation in AMN). These discrep-
ancies have prompted the search for modifying genes,
however, as yet without conclusive results (Moser, 1997).
Unlike Multiple Sclerosis (MS), the most common human
demyelinating disease of the central nervous system (CNS),
0165-5728/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0165-5728(02)00445-9
* Corresponding author. Tel.: +49-228-287-5712; fax: +49-228-287-
5024.
E-mail address: [email protected] (S. Schmidt).
www.elsevier.com/locate/jneuroim
Journal of Neuroimmunology 135 (2003) 148–153
no firm association of X-ALD with HLA class II alleles has
been established (McGuiness et al., 1997; Moser, 1997;
Berger et al., 1995). Although several lines of evidence
suggest that excessive production of tumor necrosis factor-
alpha (TNFa) is pathogenetically relevant in the cerebral
form of X-ALD, the exact molecular mechanisms of CNS
demyelination have remained enigmatic (Aubourg et al.,
2000). Nonetheless, the hitherto unexplained contribution
of the immune system to the phenotypic differences in X-
ALD patients suggests that modifying genes in ‘‘immunor-
elevant’’ regions such as cytokine and myelin protein genes
might be involved in phenotype modification of X-ALD.
As one example of a disease-modifying genetic varation
of a cytokine gene, the so-called C allele of a variable
number tandem repeat (vntr) polymorphism located in the
3V flanking region of the interleukin-6 (IL-6) gene (IL-6)
has been shown to be associated with delayed onset of
Alzheimer’s disease (Papassotiropoulos et al., 1999) and a
benign course of MS in Sardinian patients (Vandenbroeck et
al., 2000). In accordance with the latter finding, a significant
underrepresentation of the IL-6 C allele was observed in
patients with progressive forms of MS (Schmidt et al.,
2000). Here, we tested the hypothesis if the IL-6 C allele
is also associated with distinct adult phenotypes of X-ALD.
The demonstration of myelin oligodendrocyte glycopro-
tein (MOG)-specific antibodies and antibody-dependent
immune effector mechanisms in lesion formation of exper-
imental autoimmune encephalomyelitis (EAE) (Stefferl et
al., 2000) and within inflammatory lesions of MS patients
(Raine et al., 1999) has highlighted the possible pathoge-
netic contribution of humoral immune responses in human
CNS demyelinating disease. We recently demonstrated
elevated levels of autoantibodies against a recombinant
preparation of MOG in various phenotypes of X-ALD
(Schmidt et al., 2001) confirming previous studies indicat-
ing that MOG-specific antibody responses are not confined
to MS (Reindl et al., 1999). Since cellular and humoral
MOG-specific immune responses in EAE are strongly
dependent on the genetic background of the experimental
animals (Stefferl et al., 2000), we tested the hypothesis if
anti-MOG autoantibody responses in X-ALD patients are
associated with HLA class II alleles and a naturally occur-
ring tetranucleotide (TAAA)n repeat polymorphism in the 3Vflanking region of the MOG gene.
2. Patients and methods
2.1. X-ALD patients
Serum and peripheral blood samples were obtained from
72 X-ALD patients recruited from Sachsisches Krankenhaus
Hubertusburg, Wermsdorf. X-ALD was diagnosed by deter-
mination of increased serum levels of very long chain fatty
acids (C22, C24, C26) and their respectice ratios (C26:C22,
C24:C22). The assignment of clinical phenotypes of X-ALD
patients was based on clinical history, neurological and
electrophysiological examination as well as magnetic reso-
nance imaging (MRI) (Moser, 1997). Cranial MRI was in
particular used to further differentiate between three AMN
subtypes (Kumar et al., 1995): Normal brain MRI and
thoracic cord atrophy (pure AMN), pyramidal or cortico-
spinal tract hyperintense lesions with otherwise normal brain
MRI and thoracic cord atrophy (AMN with tract involve-
ment), and white matter lesions in various brain regions
combined with pyramidal and corticospinal tract involve-
ment and thoracic cord atrophy (ALMN). A definite clinical
phenotype characterization was available in 70 X-ALD
patients who were selected for further statistical analysis.
16 patients represented pairs of heterozygous symptomatic
mothers and their affected sons. All but three patients were of
German Caucasian origin. For statistical analysis, AMN
patients were divided into two groups according to their
clinical subtypes, namely pure AMN and ALMN/AMN with
tract involvement. The clinical phenotypes and demographic
data of the 70 X-ALD patients included in the study are
given in Table 1. For the frequency distribution of IL-6 C
allele, a sample of 73 healthy individuals [32 males (44%),
41 females (56%)] with a mean age of 38.2F 6.7 years
(range 19–68 years) selected randomly from a large pop-
ulation-based sample participating in a family study of
dementia and depression was included (Heun et al., 2001).
All subjects were of German ancestry living in the federal
state of Nordrhein–Westfalen. All patients and control sub-
jects gave informed consent to participate in the study, and
the study was approved by the local ethics committees.
3. Genetic analysis
3.1. Analysis of IL-6 vntr polymorphism
Leukocyte DNA was isolated using standard protocols.
The vntr polymorphism, situated in the 3Vflank of IL-6 was
Table 1
Demographic and clinical data of X-ALD patients
n Age
(years)
Age of
onset (years)
All patients 70 42.2F 11.9
(19–68)
30.9F 13.2
(8–65)
Pure AMN 31 39.6F 8.8
(21–59)
27.0F 8.2
(13–41)
ALMN/AMN with
tract involvement
15 43.9F 12.2
(30–66)
29.3F 14.0
(8–58)
Female
heterozygotes
16 52.2F 10.9
(33–68)
44.1F11.5
(20–65)
CALD 4 35.5F 5.9
(28–42)
13.3F 7.5
(8–22)
Addison 2 24.5F 7.8
(19–30)
n.k.
Asymptomatic 2 22.0F 1.4
(21–23)
n.a.
n.a.: not applicable; n.k.: not known.
S. Schmidt et al. / Journal of Neuroimmunology 135 (2003) 148–153 149
studied as previously described (Papassotiropoulos et al.,
1999). The following oligonucleotide primers were used:
5V-GCA ACT TTG AGT GTG TCA CGT GAA-3V(for-(forward) and 5V-TGA CGT GAT GGA TGC AAC AC-3V(reverse). After polymerase chain reaction (35 cycles of 1
min at 94 jC, 1 min at 60 jC, and 1.5 min at 72 jC),amplification products were separated by 7% polyacryla-
mide gel electrophoresis and visualized by ethidium bromide
staining. Alleles were designated as previously described
(Bowcock et al., 1989). Four alleles (A–D) coding for
variants of four different lengths were identified. Allele A
yielded a product with the approximate size of 760 base pairs
(bp); the approximate sizes of alleles B, C, and D were 680,
640 and 610 bp, respectively. Only the presence or absence
of the IL-6 C allele was considered for statistical analysis.
3.2. Analysis of MOG gene (TAAA)n polymorphism
The polymorphic tetranucleotide repeats in exon 8 of the
MOG gene were analyzed as previously described (Malfroy
et al., 1995). Briefly, the oligonucleotide primers MOG50
(5V-ATCTTTCCTTCCTCTCATCC-3V) and MOG52 (5V-GGCTGGAGTAGAGGGAG-3V) were used for the tetranu-
cleotide repeat. Twenty-five cycles of PCR were performed
at the following conditions: 30 s at 94 jC, 30 s of 54 jC,and 30 s at 72 jC. In addition, an additional 12-cycle PCR
was performed using the oligonucleotide primer MOG51
(5V-CCAGGAGGCAGAGGTTG-3V) under the same PCR
conditions. Amplification products were loaded onto 6%
denaturing polyacrylamide gels with the GS-350 internal
lane standard (Applied Biosystems) and analyzed on ABI
373 DNA sequencing system. Seven alleles (A–G) coding
for variants of seven different lengths were identified. Allele
A yielded a product with the approximate size of 230 bp,
the approximate sizes of alleles B, C, D, E, F and G were
226, 222, 218, 214, 210 and 206 bp, respectively.
3.3. Analysis of HLA-DRB1*, -DQB1* alleles
HLA class II alleles (HLA-DRB1*, -DQB1*) were
determined according to established protocols (Olerup and
Zetterquist 1992; Olerup et al., 1993). For subtyping of
DRB1* genes allele specific primer mixes were used
(Dynal, Oslo, Norway). HLA alleles were classified accord-
ing to the nomenclature proposed by the World Health
Organization Nomenclature Commitee (Bodmer et al.,
1994). The frequency distribution of HLA-DRB1*, -DQB1*
alleles was compared to a previously published cohort of
174 healthy Caucasian subjects (Ferencik and Grosse-
Wilde, 1997).
3.4. Determination of anti-MOG antibodies
Recombinant human MOG corresponding to the extrac-
ellular IgG-like domain (rhMOGIgD) was expressed and
purified as previously outlined (Reindl et al., 1999; Haase
et al., 2001; Schmidt et al., 2001) followed by ion exchange
chromatography on a strong cationic membrane system
(Sartobind, Sartorius, Gottingen, Germany). Serum anti-
bodies directed against rhMOGIgD were determined by
immunoblotting as previously described (Reindl et al.,
1999; Haase et al., 2001; Schmidt et al., 2001).
3.5. Statistical analysis
Statistical analysis was performed with the SPSS software
package (SPSS, Chicago, IL, USA). Group comparisons
were calculated by one-way analysis of variance (ANOVA).
The presence of allelic polymorphisms was compared by
Pearson’s v2 test. Logistic regression was performed to test
for interactions between genotypes, phenotypes, HLA-
DRB1* alleles, MOG gene (TAAA)n polymorphism, IL-6
C allele, and anti-MOG-antibody responses.
All investigators performing the genetic analyses were
blinded with regard to the presence of anti-MOG antibodies
and the clinical phenotype of X-ALD patients.
4. Results
4.1. IL-6 vntr polymorphism
Genotyping of IL-6 vntr polymorphism was performed in
68 patients. The frequency distribution of IL-6 C allele in X-
ALD patients and healthy donors is given in Table 2. The
IL-6 C allele was equally distributed between X-ALD
patients and healthy controls. However, stratification of X-
ALD patients according to their clinical phenotypes
revealed that IL-6 C allele was more frequent in patients
with pure AMN as compared to other X-ALD phenotypes
and healthy controls. This difference, however, did not
reach statistical significance ( p = 0.081).
4.2. MOG gene (TAAA)n polymorphism
Genotyping of MOG gene (TAAA)n tetranucleotide
polymorphisms was performed in 68 patients. The fre-
quency distribution of MOG gene (TAAA)n alleles in X-
ALD patients is given in Table 3. The allelic distribution of
Table 2
Frequency and distribution of IL-6 C allele
C allele present C allele absent
All patients 26/68 (38.2%) 42/68 (61.8%)
Pure AMN 15/29 (51.7%) 14/29 (48.3%)
ALMN/AMN with
tract involvement
5/15 (33.3%) 10/15 (66.7%)
Female heterozygotes 5/16 (31.3%) 11/16 (68.7%)
CALD 1/4 (25%) 3/4 (75%)
Addison 0/2 2/2 (100%)
Asymptomatic 0/2 2/2 (100%)
Healthy donors 23/73 (31.5%) 50/73 (68.5%)
S. Schmidt et al. / Journal of Neuroimmunology 135 (2003) 148–153150
MOG gene (TAAA)n alleles was not significantly different
as compared to the previously published allelic distribu-
tions in healthy Caucasian controls (Malfroy et al., 1995)
with the 226, 222 and 218 bp alleles being the most
common allelic polymorphisms. Two patients were homo-
zygous for the 230 bp, two for the 226 bp, and two for the
218 bp allele. One patient was homozygous for the 222 bp,
and one for the 210 bp allele. There was no association of
MOG gene (TAAA)n alleles with distinct clinical pheno-
types.
4.3. HLA-DRB1*, -DQB1* alleles
The frequency distribution of HLA-DRB1* alleles is
given in Table 4. HLA-DRB1*04 alleles (32.9%) were most
common in the whole group of X-ALD patients. HLA-
DRB1*1501 (13.6%), -DRB1*0401 (12.9%), -DRB1*0101
(11.4%), and -DRB1*0301 (10.7%) as well as -DRB1*1301
(10.7%) were the most common single alleles. This
distribution was not statistically significantly different
from that of healthy Caucasian controls as previously
published (Ferencik and Grosse-Wilde, 1997). After exclu-
sion of heterozygote mothers, HLA-DRB1* frequency
distribution remained essentially the same with HLA-
DRB1*04 alleles occurring in 24.4% of patients. Notably,
HLA-DRB1*1401 alleles were underrepresented in X-ALD
patients ( p < 0.05).
As for the DQ-locus HLA-DQB1*0301 (23.7%), -DQB1*
0501 (12.6%), -DQB1*0602 (14.1%), and -DQB1*0603
(11.1%) were the most common single alleles.
There was no association of HLA-class II alleles with
clinical phenotypes.
4.4. Anti-MOG antibodies and their association with MOG
gene (TAAA)n polymorphism
The presence of anti-MOG antibodies was analyzed in 54
X-ALD patients. Anti-MOG antibodies were detectable in
17/54 sera (31.5%). Nine patients with anti-MOG antibodies
had AMN, two ALMN/AMN with tract involvement, four
were female heterozygotes, one had Addison’s disease and
one was asymptomatic.
While the presence of anti-MOG antibodies was neither
associated with clinical phenotypes, age of onset, duration
of disease, HLA-class II alleles or IL-6 C allele, a statisti-
cally significant association was established with the 226 bp
(TAAA)n MOG gene polymorphisms ( p < 0.05).
5. Discussion
The present study demonstrates no apparent association
of HLA class II alleles, IL-6 C allele and (TAAA)n MOG
gene polymorphisms with adult clinical phenotypes of X-
ALD. While no association of clinical phenotypes with
HLA alleles and (TAAA)n MOG gene polymorphisms
was detectable, the presence of serum anti-MOG anti-
bodies was associated with the 226 bp (TAAA)n MOG
gene polymorphism but not with distinct clinical pheno-
types.
5.1. Clinical considerations
The phenotypic heterogeneity of X-ALD makes the
existence of disease modifying factors or genes plausible.
Table 4
Frequency and distribution of HLA-DRB1* alleles in X-ALD patients
HLA- All patients Pure AMN ALMN/AMN tract Female heterozyg CALD Addison Asymptomatic
DRB1*01 17/70 (24.3%) 7/31 (22.6%) 4/15 (26.7%) 2/16 (12.5%) 3/4 (75%) 0/2 1/2 (50%)
DRB1*15 18/70 (25.7%) 11/31 (35.5%) 4/15 (26.7%) 2/16 (12.5%) 0/4 1/2 (50%) 0/2
DRB1*0301 13/70 (18.6%) 3/31 (9.7%) 3/15 (20%) 6/16 (37.5%) 1/4 (25%) 0/2 (%) 0/2
DRB1*04 23/70 (32.9%) 8/31 (34.8%) 7/15 (46.7%) 5/16 (31.3%) 1/4 (25%) 1/2 (50%) 1/2 (50%)
DRB1*0701 11/70 (15.7%) 6/31 (19.4%) 0/15 3/16 (18.8%) 1/4 (25%) 1/2 (50%) 0/2
DRB1*08 4/70 (5.7%) 2/31 (6.5%) 1/15 (6.7%) 1/16 (6.3%) 0/4 0/2 0/2
DRB1*0901 0/70 0/31 0/15 0/16 0/4 0/2 0/2
DRB1*11 14/70 (20%) 4/31 (12.9%) 6/15 (40%) 3/16 (18.8%) 1/4 (25%) 0/2 0/2
DRB1*01201 5/70 (7.1%) 4/31 (12.9%) 0/15 1/16 (6.3%) 0/4 0/2 0/2
DRB1*13 20/50 (28.6%) 11/31 (35.5%) 1/15 (6.7%) 6/16 (37.5%) 1/4 (25%) 1/2 (50%) 0/2
Table 3
Frequency and distribution of MOG gene (TAAA)n polymorphism
230 bp 226 bp 222 bp 218 bp 214 bp 210 bp
All patients 25/68 (36.8%) 29/68 (42.6%) 26/68 (38.2%) 33/68 (48.5%) 6/68 (8.8%) 9/68 (5.7%)
Pure AMN 12/30 (40%) 11/30 (36.7%) 12/30 (40%) 13/30 (43.3%) 1/30 (3.3%) 5/30 (16.7%)
ALMN/AMN tract 5/15 (33.3%) 8/15 (53.3%) 5/15 (33.3%) 8/15 (53.3%) 2/15 (13.3%) 1/15 (6.7%)
Female heterozygotes 5/16 (31.3%) 6/16 (37.5%) 8/16 (50%) 8/16 (50%) 2/16 (12.5%) 2/16 (12.5%)
CALD 2/3 (66.7%) 2/3 (66.7%) 0 1/3 (33.3%) 0 1/3 (33.3%)
Addison 1/2 (50%) 1/2 (50%) 0 2/2 (100%) 0 0
Asymptomatic 0 1/2 (50%) 1/2 (50%) 1/2 (50%) 1/2 (50%) 0
S. Schmidt et al. / Journal of Neuroimmunology 135 (2003) 148–153 151
Paradigmatically, CALD and AMN emerge as distinct
clinical phenotypes with widely different histopathological
features and prognostic implications in the same kindred
harboring identical mutations in the X-ALD gene (Moser,
1997). The complexity of clinical phenotype generation in
X-ALD is further highlighted by the existence of distinct
subtypes even within the AMN phenotype. Almost half of
AMN patients exhibit signs of cerebral demyelination on
MRI (Kumar et al., 1995). This finding is of prognostic
relevance since patients with ALMN progress more rapidly,
and may even convert into CALD (Moser, 1997; van Geel et
al., 2001). The question if AMN patients with tract involve-
ment represent a distinct subgroup of AMN patients or
merely a more advanced variant of pure AMN is currently
unsolved (Kumar et al., 1995; Moser, 1997).
5.2. IL-6 vntr polymorphism
Recently, several independent studies reported disease
modifying effects of genetic variations of IL-6. First, IL-6 C
allele is associated with delayed onset of Alzheimer’s
disease (Papassotiropoulos et al., 1999). Second, the same
allelic polymorphism is associated with a benign course of
MS in Sardinian patients (Vandenbroeck et al., 2000), and is
partially protective in patients with systemic lupus eryth-
ematodes (Linker-Israeli et al., 1999). This disease-modify-
ing effect of IL-6 C allele was further confirmed by a
previous study of our group demonstrating that IL-6 C allele
is underrepresented in MS patients with both primary and
secondary progressive MS (Schmidt et al., 2000). Here, we
demonstrated that IL-6 C allele is more frequent in X-ALD
patients with pure AMN although not reaching statistical
significance. However, while an overrepresentation of IL-6
allele would nicely fit into the context of the aforementioned
studies, a protective effect of IL-6 C allele on the course of
X-ALD is unlikely, since the frequency distribution of IL-6
C allele is almost identical in patients with ALMN/AMN
with tract involvement (i.e. patients with a less favorable
prognosis) and healthy donors. Moreover, in contrast to SLE
and MS, the pathogenetic role of IL-6 in X-ALD has not
been established.
5.3. HLA-DRB1*, -DQB1* alleles
MS, the most common demyelinating disease of the
CNS, is associated with the HLA alleles DRB1*1501 and
DQB1*0602 in northern Europeans (Olerup and Hillert,
1991). The histopathological similarities of demyelinating
lesions in MS and cerebral forms of X-ALD (Moser, 1997)
gave rise to speculations that X-ALD might also be asso-
ciated with certain HLA class II alleles. However, previous
studies investigating this association yielded conflicting
results. Whilst an association of HLA-DRB1*16 alleles
was reported in a group of 29 X-ALD patients (Berger et
al., 1995), this finding was not confirmed in a larger study
of 83 X-ALD (McGuiness et al., 1997). Similarly, the
present study encompassing 70 X-ALD patients failed to
demonstrate an association of certain HLA-DR and -DQ
alleles with X-ALD in general and clinical phenotypes in
particular. Moreover, no association between HLA alleles
and serum anti-MOG antibody responses was detectable.
5.4. Anti-MOG antibodies and their association with MOG
gene (TAAA)n polymorphism
The human MOG gene is located within the MHC region
on chromosome 6p21.3–p22 (Pham-Dinh et al., 1995).
Naturally occurring polymorphisms of the MOG gene were
first identified in exon 1 as a trinucleotide (CTC)n and in the
3V flanking region (exon 8) as a tetranucleotide (TAAA)nrepeat motif (Roth et al., 1995b). Most recently, four novel
sequence variations of the MOG gene have been identified
(Gomez-Lira et al., 2000). The external localization of
MOG in the myelin sheath, its restriction to the CNS, and
the accumulated experimental evidence that cellular and
humoral immune responses directed against MOG contrib-
ute to myelin breakdown in MS (Raine et al., 1999; Stefferl
et al., 2000) make this protein an attractive candidate as an
antigenic target not only in MS but also in cerebral forms of
X-ALD. Based on this assumption, we previously inves-
tigated anti-MOG antibody responses in serum of X-ALD
patients (Schmidt et al., 2001). In the present study, MOG-
specific autoantibodies were detectable in 17/54 patients
(31.5%) confirming our previous findings that MOG-spe-
cific antibodies in X-ALD patients are detectable in a
frequency comparable to that in MS patients (Reindl et
al., 1999; Haase et al., 2001; Schmidt et al., 2001). In the
latter study, none of the 13 AMN patients, i.e. those patients
without evidence of CNS demyelination, had anti-MOG
antibodies suggesting that the presence of these antibodies
might be indicative of CNS demyelination (Schmidt et al.,
2001). However, in the larger group of 54 patients analyzed
here, anti-MOG antibodies were also detectable in patients
with pure AMN. Moreover, no association of the anti-MOG
antibody responses with any of the clinical phenotypes was
observed arguing against a discriminatory function of anti-
MOG antibodies in phenotype generation.
Since previous investigations indicated that human MOG
exists in alternatively spliced isoforms (Pham-Dinh et al.,
1995), it is tempting to speculate that minor differences in
MOG composition caused by naturally occurring polymor-
phisms might also influence the antigenicity and immune
responses against MOG. However, previous studies in MS
patients investigating a possible role of allelic variations of
the MOG gene with regard to disease susceptibility for MS
yielded negative results (Roth et al., 1995a). A recent
genetic association study revealed equal distribution of six
(including four novel) MOG gene polymorphisms in both
X-ALD patients and healthy controls (Gomez-Lira et al.,
2000). Here, we investigated the possible association of a
naturally occurring tetranucleotide (TAAA)n polymorphism
in the 3V flanking region of the MOG gene not included in
S. Schmidt et al. / Journal of Neuroimmunology 135 (2003) 148–153152
the aforementioned study with anti-MOG antibody
responses in serum. While we found a very similar fre-
quency distribution of MOG gene (TAAA)n alleles in X-
ALD patients as compared to previously published healthy
Caucasian controls (Malfroy et al., 1995), the 226 bp MOG
gene (TAAA)n polymorphism was associated with the
presence of anti-MOG antibodies in serum. However, due
to the lack of association with clinical phenotypes in X-
ALD, the clinical relevance of this finding remains to be
established.
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