Brain & Development 25 (2003) 288–290
www.elsevier.com/locate/braindev

Case report

Familial moyamoya disease in a Greek family
Dimitrios I. Zafeiriou a,*, Hidetoshi Ikeda b, Anastasia Anastasiou c, Efi Vargiami a,
Nikos Vougiouklis c, George Katzos a, Nikos Gombakis a, Georgia Gioula d,
Yoshiharu Matsushima e, Fenella J. Kirkham f
a
1st Paediatric Klinic, Aristotle University, Thessaloniki, Greece
Department of Neurosurgery, Tohoku University School of Medicine, Sendai, Japan
c
Department of Radiology, Ippokratio General Hospital, Thessaloniki, Greece
d
Department of Microbiology, Agios Dimitrios General Hospital, Thessaloniki, Greece
e
Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan
f
Neurosciences Unit, Institute of Child Health, London, UK
b

Received 26 July 2002; received in revised form 29 October 2002; accepted 6 November 2002

Abstract
Moyamoya disease (M-M) is characterized by progressive obstruction of the supraclinoid portion of internal carotid arteries and the
proximal middle, anterior and posterior cerebral arteries, associated with the formation of a characteristic net of collateral vessels in the basal
ganglia region. Clinical manifestations in childhood include transient ischaemic attacks, seizures and multiple infarcts. Approximately 7% of
M-M cases are familial. We report two affected Greek siblings with typical clinical and neuroradiological findings of M-M. Linkage analysis
of the whole family was consistent with linkage to the region 3p24-26, as previously reported in other familial Japanese M-M cases.
q 2002 Elsevier Science B.V. All rights reserved.
Keywords: Moyamoya disease; Familial; Linkage analysis; Genetics

Moyamoya disease (M-M) is characterized by progressive obstruction of the supraclinoid portion of the internal
carotid arteries and the proximal middle, anterior and
posterior cerebral arteries, associated with the formation
of a characteristic net of collateral vessels in the basal ganglia region. Clinical manifestations in childhood include transient ischaemic attacks, seizures and multiple infarcts [1]. It
is well known that approximately 7% of M-M cases are
familial [2] and M-M in the Japanese population, where
the condition is more common [1,2], is possibly linked to
chromosome 3p24-26 [3], but also to chromosomes 6 and
17q25 [4,5]. However, there is growing evidence that cases
of familial M-M do exist outside Japan and Asia [6]. We
would like to add our own experience in this field by reporting clinical and molecular data of a Greek family with two
affected male siblings.
The first patient was a 9.5-year-old male, who was
followed-up neurodevelopmentally because of mild motor
retardation (he walked at 20 months of age and since then
has demonstrated mild clumsiness, however without true
* Corresponding author. Child Neurologist, Egnatia St. 106, 54622 Thessaloniki, Greece. Tel.: 130-310-241845; fax: 130-2920-21238.
E-mail address: jeff@med.auth.gr (D.I. Zafeiriou).

pyramidal, extrapyramidal or cerebellar tract signs). He
had normal findings on cranial magnetic resonance imaging
(MRI) at the age of 3.5 years. At the age of 7 years, he
suffered two generalized tonic-clonic seizures. In spite of
anticonvulsant medication, he continued to have focal
motor seizures and then developed recurrent transient
ischaemic attacks with migraine-like headaches and
episodes of weakness of the left face and arm, which always
subsided after a period of 5–6 h. Serial MRI of the brain
demonstrated cortical infarcts in the frontal region bilaterally, as well as small areas with low signal intensity in the
basal ganglia and thalami (M-M vessels) on T2-weighted
imaging (Fig. 1). His brother, a 4.5-year-old male, presented
with focal status epilepticus, which responded to intravenous phenytoin. Computer tomography and MRI were
consistent with multiple infarcts, predominantly in the frontal regions bilaterally.
Digital subtraction angiography was performed in both
patients and revealed obstruction of the supraclinoid part
of the internal carotid artery bilaterally and of the proximal
portions of the middle, anterior and posterior cerebral
arteries, as well as formation of M-M vessels (Fig. 2).
Extensive investigation in order to exclude cardiac causes

0387-7604/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved.
doi:10.1016/S038 7-7 604(02)0022 4-3

D.I. Zafeiriou et al. / Brain & Development 25 (2003) 288–290

Fig. 1. MRI of the first patient demonstrating increased signal intensity
compatible with cortical infarcts in the frontal region bilaterally, as well
as small areas with low signal intensity in the basal ganglia and thalami (MM vessels or the ‘salt and pepper’ phenomenon) on T2-weighted imaging.

289

(transesophageal echocardiography), biochemical abnormalities (cholesterol, triglycerides and lipoproteins), infectious causes (serum titres for varicella-zoster, mycoplasma
pneumoniae, borrelia, chlamydia and helicobacter), haematological abnormalities (including antithrombin III, proteins
C and S, activated protein C resistance, heparin cofactor II,
plasminogen, factors VII and VII, folic acid, B6 and B12,
MTHFR, prothrombin 20210 and factor V Leiden mutation,
lupus anticoagulant and anticardiolipin antibodies) and
metabolic disorders (including plasma lactate and ammonia,
blood gases, plasma homocysteine, serum and urin–aminoacids, urinary organic acids, sulphite test, very long chain
fatty acids and lysosomal enzymes) did not reveal any
underlying diagnosis.
Encephaloduro–arteriosynangiosis
(EDAS)
was
performed bilaterally in both brothers (at the age of 9 and 5
years, respectively) and antiepileptic medication with phenytoin was initiated. Two years after EDAS both patients are
neurologically normal (no evidence of pyramidal, extrapyramidal or cerebellar tract involvement, normal ocular motility, normal linguistic abilities and an IQ within the normal
range), demonstrating only mild behavioural problems
together with a slightly aggressive behaviour. Regarding
antiepileptic medication, both patients are currently off therapy and the second patient is free of seizures since the acute
episode. A third asymptomatic brother (no neurodevelopmental deficits) has a normal MRI and a normal magnetic
resonance angiography (MRA) at the age of 6 years. Both
parents also demonstrate normal MRI findings and are neurologically normal with an IQ in the normal range.
Linkage analysis of the whole family was performed in
order to see if M-M in this family could be linked to the
region 3p24-26 (Table 1), as in the cases of familial M-M

Fig. 2. Digital subtraction angiography of the second patient demonstrating obstruction of the supraclinoid part of the internal carotid artery (left) and of the
proximal portions of the middle, anterior and posterior cerebral arteries, as well as formation of M-M vessels (M-M phenomenon or ‘puff of smoke’).

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D.I. Zafeiriou et al. / Brain & Development 25 (2003) 288–290

Table 1
Linkage analysis of the family with M-M disease a
Allele type

Father
Mother
Patient 1
Patient 2
Healthy brother

D3A

D3SB

D3SC

1, 2
2, 2
1, 2
1, 2
1, 2

1, 8
2, 8
1, 2
2, 8
2, 8

1, 3
5, 7
3, 7
1, 7
1, 7

a

The nearest loci responsible for the M-M disease gene at 3p are indicated as D3A, D3SB, D3SC and each pair of numbers, for example 1, 2,
represents the allele type. Two brothers (patient 2 and healthy brother)
inherited the same haplotype from their father (1 for locus D3A, 8 for
locus D3SB, and 1 for locus D3SC) and the third (patient 1) appears to
have had a recombination event between D3A and D3SB, resulting in a 1-13 haplotype, and thus sharing only the paternal D3A allele with his siblings.
This analysis is consistent with autosomal recessive inheritance with
reduced penetrance only at the D3A locus.

reported by Ikeda [3] in Japan. Although the family is too
small to generate a significant LOD score, the genetic analysis was consistent with autosomal recessive inheritance at
the D3A locus with reduced penetrance (since the healthy
sibling is haploidentical and unaffected).

To the best of our knowledge this is the first familial M-M
case in Greece and one of the few reported in patients
outside Japan. Detailed molecular genetic testing is worthwhile in these patients in order to establish possible candidate loci. Prevention or treatment of M-M based on genetic
testing might be possible in the future.

References
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