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Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype.

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(In press)
(ALD) in Only One of
Monozygotic Twins with
an Identical ALD
G. Christoph Korenke, MD," Sigrid Fuchs, PhD,$
Ernsr Krasemann, MD,? Helmuth G. Doerr, MD,§
Ekkehard Wilichowski, MD,'
Donald H. Hunnernan, PhD,* and Folker Hanefeld, MD*
We report on monozygotic twins with different clinical
phenotypes of X-linked adrenoleukodystrophy. At the age
of 10 years both boys were neurologically asymptomatic.
The first cranial magnetic resonance examination showed
normal findings in the first twin and parietooccipital demyelination in the second. The latter developed behavioral problems 9 months later, followed by visual impairment and gait ataxia. His cranial magnetic resonance
image at the age of 11 years showed progressive demyelination. In contrast, neurological status and magnetic resonance images remained normal in the first twin. The same
point mutation in exon 8 of the adrenoleukodystrophy
gene (C2203T) was detected in both boys. All genotype
examinationswere consistent with the diagnosis of monozygotic twins, suggesting that some nongenetic factors
may be important for different adrenoleukodystrophy
Korenke GC, Fuchs S, Krasemann E, Doerr HG,
Wilichowski E, Hunneman D H , Hanefeld F.
Cerebral adrenoleukodystrophy (ALD) in only one
of monozygotic twins with an identical ALD
genotype. Ann Neurol 1996;40:254-257
X-linked adrenoleukodystrophy (ALD), characterized
by impaired peroxisomal P-oxidation of very-longchain fatty acids (VLCFAs), shows a striking clinical
variation. The most frequent forms are childhood cerebral ALD (cALD, about 40% of patients) and adult
adrenomyeloneuropathy (AMN, about 40% of patients) [ l , 21. In cALD a period of unspecific symptoms such as disturbances of behavior is followed by
From the 'Department of Paediatrics and Neuropaediatrics and
t Institute of Human Genetics, University of Gotringen, Gotringen;
$Institute of Human Genetics, University of Hamburg, Hamburg;
and SDeparrmenr of Paediatrics, University of Erlangen-Nurnberg,
Erlangen, Germany.
Received Feb I , 1996. and in revised form Mar 18. Accepted for
publication Mar 22, 1996.
Address correspondence to Dr Hanefeld, Department of Paediatrics
and Neuropaediacrics, University of Gotringen, Robert-Koch-Str.
40, D-37075 Gottingen, Germany.
Copyright 0 1996 by the American Neurological Association
Fig 1. Pedigree of the family with
(Patients I and 2).
the twins, 111-I
and 111-2
rapid neurological deterioration, leading to severe neurological disability with tetraparesis [ 11. Besides these
neurological symptomatic phenotypes, there are neutologically asymptomatic phenotypes (about 20% of patients) with o r without Addison's disease. M o r e than
50 different mutations of the ALD gene [3]have been described, showing no clearly evident genotype-phenotype
correlation and the same mutation with different phenotypes within o n e kindred [4, 51. The existence of a n
additional autosomal modifier gene has been suggested
[6]. Phenotypic heterogeneity in adult monozygotic
twins with ALD, both neurologically symptomatic, has
been described [7].We report distinctly different clinical
phenotypes in monozygotic twin children.
One maternal uncle (Fig 1, 11-4) of our patients developed
ataxia, speech disturbances, and dysphagia at the age of 9
years and died 1'/z years later. His brother (11-5) had slowly
progressive spastic ataxia starting at the beginning of the
third decade of life. Ten years later AMN was diagnosed, by
the finding of elevated VLCFA levels. The twins' mother (II2), maternal aunt (11-3), and grandmother (1-1) all showed
mild symptoms of AMN with disturbances of sensibility and
reduced vibration sense.
The twins were born at the 37th week of gestation without
complications after a normal pregnancy. In both twins psychomotoric development during the first years was normal.
The first twin (Patient 1, see Fig 1, 111-1) demonstrated
right-handedness; the second twin (Patient 2, see Fig 1, III2) developed left-handedness. VLCFA levels measured at the
age of 6 in the course of family examination were found to
be elevated. Endocrinological examination revealed Addison's
disease in both twins, with highly elevated plasma corticotropin levels (>1,450 ng/liter; normal <50) and absent cortisol
response to intravenous corticotropin stimulation. Therapy
with hydrocortisone was initiated. Dietary treatment with
glycerol trioleate and glycerol trierucate had been started but
in both patients there was no decrease in plasma VLCFA
levels, possibly because of poor compliance.
Fig 2. T2-weighted axial magnetic rrsonancr image of
Patient i at the age cf I I years, showing no demyelinntion.
In Patient 1 magnetic resonance imaging (MRI) showed
normal findings at the ages of 10 and 11 years (Fig 2). Neurological and neuropsychological examinations revealed conipletely normal results.
In Patient 2 the first cranial MRI at the age of 10 years
revealed parietooccipital and beginning frontal demyelination
in the neurologically asymptomatic boy. Loss of concentration was observed 9 months later, followed by visual impairment and gait ataxia after 2 months. Cranial MRI at the age
of 11 years showed progressive demyelination (Fig 3) with
the typical marginal gadolinium enhancement. The typical
difference between verbal I Q (99) and performance IQ (48),
resulting in a subnormal full-scale I Q (68), was demonstrated
on the Hamburg-Wechsler Intelligence Scales for Children.
VLCFA measurements and molecular genetic analysis were
performed as described previously [4,8, 91.
Examination of Monozygosity
T h e twins had one chorion a n d one placenta. By definition they are monozygotic. Furthermore they showed
identity in red blood cell antigens-ABO
(0),Rh (D
positive, Ccee), a n d Kell (K-, kk-and
HLA types A
(A2,A3), B (B44(12,w4), B 62(15,w6)), C (cw9(3)),
and D (DR 15(2), DQ G(1)). Additional HLA geno-
Brief Communication: Korenke et
Adrenoleukodystrophy in Twins
mutation. Mitochondria1 DNA analysis of leukocytes
showed no structural rearrangements in either patient
(delecions, duplications) or point mutations at nucleotides 3243, 8344, and 8993.
We describe the ALD defect in identical twins with
Fig 3. T2-weighted axial magnetic resonance image o f
Patient 2 a t the age of 11 years, showing-progressive extension of parietooccipital and jontal demyelination.
typing revealed identical alleles for DR B1 * 1501-*
1503/DR B1 * 1601-* 1603, * 1605-* 1606 and DR
B5*0101-*0203/DR B5*0101-*0203. Molecular analysis of 20 different genomic microsatellites on chromosomes X, 4, 16, 22, and 7 showed identical DNA repeats for both twins. The probability for monozygosity
in these twins is therefore more than 99.9%.
Very-Long-Chain Fat9 Acids
VLCFA levels were elevated significantly in both patients:
Patient 1--26:0, 2.26 nmol/ml; 24:0/22:0, 1.25; and
26:0/22:0, 0.080.
Patient 2-26:0, 2.94 nmol/ml; 24:0/22:0, 1.31; and
26:0/22:0, 0.095.
Control Ievels-2G:O,
0.83 _t 0.46 nmol/ml; 24:0/22:
0, 0.84 ? 0.08; and 26:0/22:0, 0.013 _t 0.009 [l].
Molecular Genetic Analysis
Sequence analysis of the ALD gene revealed an identical missense point mutation in exon 8 in both patients
(C2203T), which results in an exchange of serine by
leucine (S6OGL) in the ALD protein. The mother,
grandmother, and aunt were heterozygous for the same
256 Annals of Neurology
Vol 40
No 2 August 1996
the identical genotype but with a discordant clinical
course. The second left-handed twin developed classic
cALD at the age of 10 years while his right-handed
first-born brother remained healthy. Phenotypic heterogeneity has been described in adult monozygotic
twins with AMN and cerebral demyelination, extensive
in one and mild in the other twin [7].The identical
gene defect was presumed but not examined.
The reason for the intrafamilial phenotypic variability in X-linked ALD is unknown. This variability could
not be related to the primary defect of the ALD gene,
the expression of the ALD protein [lo], or plasma
VLCFA level. Segregation analysis indicated a 20 : 1
likelihood that there is an autosomal modifier gene that
determines whether an ALD mutation will manifest as
ALD or AMN [6].
The S606L mutation reported here has already been
described in a patient with ALD and Addison's disease
[l 11. Since the nuclear genotype is identical, other factors must be responsible for the different phenotype.
A heteroplasmic mitochondrial DNA point mutation
in the mother could result in different tissue-specific
heteroplasmy in the 2 boys. Although the most common pathogenic mitochondrial DNA mutations were
excluded, the possibility of a mitochondrial genome
involvement cannot be completely eliminated.
A causal relation to environmental factors seems unlikely in these twins. They grew up in the same family,
spent nearly all their time together, had very similar
eating habits, and had a similar history of infections.
Epitope differentiation of T and B cells by fluorescenceactivated cell sorter analysis revealed no significant differences in our patients, as described for type I diabetes
in monozygotic twins [ 121. The different handedness
of our twins is a puzzling and intriguing observation.
An association between sinistrality autoimmune diseases
had been postulated [13], but remains unproved.
Presently no satisfactory explanation can be given
for the different phenotypes observed in the identical
twins carrying the identical ALD gene. One might postulate that the healthy twin will also develop neurological symptoms in the future, but the lack of MRI alterations at the age of 11 years in the first twin makes
the onset of neurological symptoms in the next I or
2 years unlikely. In later years cALD develops only in
a small percentage of male gene-carriers. Monozygotic
twins with adult Refsum's disease [ 141 as well as rnonozygotic twins with metachroniatic leukodystrophy [ 151
showed similar clinical courses. The search for the fac-
tors that influence the phenotypic differentiaton of Xlinked ALD remains of utmost importance for the
prognosis and treatment of ALD.
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