Brief Communications
Moyamoya Syndrome in a Splenectomized Patient
With ␤-Thalassemia Intermedia

and stenotic lesions were not progressive. The pathogenesis of the moyamoya
vasculopathy in ␤-thalassemia is discussed.

ABSTRACT

Case Report

We describe a 14-year-old Japanese girl with ␤-thalassemia intermedia who developed moyamoya syndrome after splenectomy.
This patient had compound heterozygous mutations of the
␤-globin gene and received occasional transfusions. After splenectomy at 12 years of age, she transiently required partial exchange
transfusions for leukoerythroblastosis but attained transfusion
independence. Two years after the splenectomy, transient ischemic
attacks occurred repeatedly with right hemiparesis or left paresthesia. Magnetic resonance imaging revealed bilateral stenosis of
the internal carotid arteries and dilatation of the perforating
branches with the formation of moyamoya vessels but not infarctions. The strict adherence to aspirin and dipyridamole has led to
no stroke or progression of the vasculopathy for 8 years. Moyamoya
disease has been reported in a patient with ␤-thalassemia major.
Cerebral vasculopathy can be a rare but grave consequence of the
thromboembolic complications in ␤-thalassemia major/intermedia.
(J Child Neurol 2006;21:75–77).

Moyamoya disease is an idiopathic cerebral vasculopathy characterized by
the bilateral occlusion of intracranial carotid arteries and proximal portions
of anterior and/or middle cerebral arteries with a collateral network of telangiectatic vessels resembling a “puff of smoke” (“moyamoya”) in adjacent
areas.1 Ischemic attacks of hemiplegia or seizures constitute the major
presentation in childhood, whereas subarachnoid hemorrhage occurs more
frequently in adults. The progressive nature of the disease leads to unfavorable neurologic outcomes without surgical intervention to reconstitute
the cerebral circulation.2 The diagnosis of moyamoya disease but not moyamoya syndrome is made in patients with no underlying disease or identifiable cause of vasculitis, atherosclerosis, and malformations for
understanding the etiology and pathophysiology of vasculopathy.
The ␤-thalassemias are a heterogeneous group of inherited hemoglobin
disorders characterized by reduced synthesis of ␤-globin chains and primarily
affecting individuals in malaria-endemic areas.3 Homozygous or compound
heterozygous mutations of the ␤-globin gene lead to severe anemia with ineffective erythropoiesis and hemolysis as the major or intermediate phenotype. Splenectomy is not recommended for thalassemic patients without
hypersplenism because of its limited effects on the increase in the hemoglobin concentration and the thromboembolic complications. It is difficult
to determine the degree of hypersplenism affecting the severity of the anemia caused by the unbalanced production of globin chains. There has been
renewed interest in the thromboembolic complication of thalassemias
because a subclinical hypercoagulable state has already started in children.4,5 Cerebrovascular accidents are the major complication of sickle
cell disease and are accompanied by narrowing and occlusion of the internal carotid arteries with the formation of moyamoya vessels.6,7 On the
other hand, only one case of an association between thalassemia and moyamoya disease has been reported.8
We describe a 14-year-old Japanese girl with ␤-thalassemia who developed moyamoya syndrome after splenectomy. There were no ischemic
attack recurrences during the antiplatelet therapy. The moyamoya vessels

A 14-year-old Japanese girl with ␤-thalassemia intermedia visited us owing
to consecutive episodes of transient right hemiparesis. An aplastic crisis in
a parvovirus B19 infection at 6 years of age had led to the diagnosis of
␤-thalassemia with compound heterozygous mutations IVS-2 654 C>T and
IVS-2 1 G>A.9 Her parents and brother had either one of the mutations,
exhibiting a minor phenotype. There was no family history of cerebral vascular accidents. The patient underwent splenectomy at 12 years of age
because of the monthly transfusions and splenomegaly. One month and 5
months after the splenectomy, headache and general malaise associated with
leukoerythroblastosis occurred but were controlled by temporary partial
exchange transfusions. Her hemoglobin levels then remained at more than
8.0 g/dL without any following transfusion. Aspirin therapy was continued
for postsplenectomy thrombocytosis.
On the visit, physical examination revealed a small, slightly pale, and
icteric girl of 135.5 cm in height (–3.0 SD) and 28.7 kg in weight (–2.7 SD).
Her pulse rate was 114/minute, and her blood pressure was 110/48 mm Hg.
Chest auscultation was normal. The liver was palpated 5 cm below the right
costal margin. The spleen had been resected. Neurologic examinations
defined no abnormality. The peripheral blood counts showed leukocytes 11.72
⫻ 109/L, erythrocytes 3080 ⫻ 109/L, hemoglobin 8.5 g/dL, hematocrit 26.9%,
reticulocytes 68%, nucleated erythrocytes 22.86 ⫻ 109/L, and platelet count
958 ⫻ 109/L. Marked poikilocytosis and Howell-Jolly bodies were found.
Blood chemistry indicated hemolysis, lactate dehydrogenase 802 IU/L, and
indirect bilirubin 3.8 mg/dL. Coagulation studies revealed subnormal activities of protein C (40%; reference range 75–131), protein S (58%; reference
range 70–118), and plasminogen (68%; reference range 80–128) and an
increase in thrombin-antithrombin complexes (3.4 ng/mL; reference range
0–3.0). There were no abnormalities in other parameters, including antithrombin III, lupus anticoagulant, and anticardiolipin antibodies. Her family members showed normal coagulation studies. Electroencephalographic and
cardiologic studies were normal. Computed tomography revealed no brain
lesions with widening of the diploic spaces of the skull bone. Magnetic resonance imaging revealed no infarctions but high signal intensities of bilateral basal ganglia surrounded by multiple small signal voids in T1-weighted
images, which indicated iron overload and collateral small vessels (Figure
1). Magnetic resonance angiography showed bilateral and left dominant narrowing of the supraclinoid portions of the internal carotid arteries and
dilatation of the thalamoperforating branches, along with the formation of
collateral vessels (Figure 2). These findings were compatible with stage III
moyamoya disease.10 A close interview disclosed 1 week of discontinuation
of aspirin therapy before the attack. Transient left paresthesia and hypoxic
attacks recurred a month after the resumption of aspirin therapy. Combined
administration of dipyridamole has resulted in no attack for 8 years.
Follow-up magnetic resonance angiograms showed no progression of the
stenotic lesions and moyamoya vessels. She has been free of any neurologic
deficits.

Discussion
Moyamoya syndrome occurs in patients with brain tumors, vascular malformations, or vasculitis after irradiation, infections, and head trauma. It
can be associated with various inherited disorders, that is, neurofibromatosis, tuberous sclerosis complex, Down syndrome, and Alagille syndrome, along with some anemias.1 Patients with homozygous hemoglobin
S occasionally develop cerebral infarctions and narrowing or occlusion of
the internal carotid arteries, with the moyamoya pattern as the most common arteriographic finding.6,7,11–13 The progressive vasculopathy can be a consequence of the flow in the vasa vasorum being obstructed by sickle cells,
which leads to ischemia in the walls of the internal carotid arteries, intimal

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76

Journal of Child Neurology / Volume 21, Number 1, January 2006

Figure 2. A Brain magnetic resonance angiogram showing bilateral
narrowing of the supraclinoid portions of the internal carotid arteries
with left predominance (arrows) and dilatation of the thalamoperforating branches, along with the formation of bilateral collateral vessels. B Enlarged view of the left moyamoya vessels (circle). These
findings are consistent with stage III moyamoya disease.

Figure 1. Brain magnetic resonance image showing no infarctions but
high signal intensities in bilateral basal ganglia surrounded by multiple small round voids and widening of the diploic spaces of the skull
bone (T1-weighted image [repetition time: 560.0 milliseconds; echo time:
14.0 milliseconds]).

proliferation, and occlusion but not exclusively of the direct obstruction of
small cerebral vessels by the cells. Moyamoya syndrome has been reported
in patients with hereditary spherocytosis14 and Fanconi anemia.15 Ischemic
strokes might be associated with other types of anemia, including iron
deficiency anemia7 and Diamond-Blackfan anemia.16 There is a high incidence of cerebral thrombosis in ␣- and ␤-spectrin–deficient mice with
hereditary spherocytosis.17 The increased blood flow caused by anemia,
together with less deformable red cells, can lead to progressive endothelial proliferation and subsequent vascular occlusion. There has been one
case report of the association of moyamoya vasculopathy and ␤-thalassemia.8 A 5-year-old girl with ␤-thalassemia major presented with hemiconvulsions and hemiplegia with cerebral infarctions and bilateral occlusion
of the internal carotid arteries with moyamoya vessels and suffered from
aphasia and spastic paraplegia as sequelae.8 Unlike in our patient, the
ischemic attacks in the patient with the major phenotype occurred prior to
splenectomy. A chronic hypercoagulable state has been a focus of constant
attention in ␤-thalassemia major/intermedia.4,5 An excess of ␣-chain molecules and their derivatives, including hemin, results in damage to the erythrocyte membranes in ␤-thalassemia via oxidative stress. The membrane
damage induces increased surface expression of anionic phospholipids, such
as phosphatidylserine, which incites the platelet activation and the procoagulant effect of thalassemic erythrocytes.5 Patients with ␤-thalassemia or
sickle cell anemia share the membrane phospholipid abnormalities of erythrocytes and exhibit similar coagulation profiles, including elevated plasma
levels of thrombin-antithrombin complexes and decreased levels of proteins
C and S.5 The present patient showed the typical coagulation profile of ␤thalassemia. On the other hand, overt thrombotic events are less common
in ␤-thalassemia major/intermedia cases than in those with homozygous
hemoglobin S (sickle cell crisis).5 Sickle cells are less deformable than tha-

lassemic erythrocytes to obstruct the microcirculation. Patients with ␤-thalassemia intermedia who do not receive transfusions regularly have a much
higher incidence of thrombotic events than patients receiving regular transfusions.5 Splenectomy usually increases the risk of strokes and embolism
owing to thrombocytosis and hyperlipidemia. In this setting, postsplenectomy thrombocytosis and weaning from transfusions augmented the hypercoagulability associated with the abnormal erythrocyte rheology and might
have elicited the formation of moyamoya vessels in our patient with intermediate thalassemia. No ischemic attacks soon after splenectomy, when transient leukoerythroblastosis occurred, might indicate the later development
of the cerebral vasculopathy. However, it remains undetermined whether
the vascular changes started before or after splenectomy because magnetic
resonance angiography was not performed prior to the splenectomy. Cerebral vasculopathy in the first reported case with ␤-thalassemia was described
as moyamoya disease but not moyamoya syndrome.8 On the other hand, Peerless raised the possible risk of moyamoya syndrome in thalassemia based
on an epidemiologic study in North America.18 The bilateral vascular lesion
in our patient was not progressive after antiplatelet therapy. The present
observation might indicate a potential role of hemoglobinopathy in the
etiopathogenesis of moyamoya vasculopathy, as well as a caveat for the management of splenectomized patients with ␤-thalassemia.

Acknowledgments
We thank Dr Y. Matsushima (Division of Neurosurgery, Hamanomachi Hospital,
Fukuoka, Japan) for the helpful discussion, Mr T. Kanemaru (Morphology Core
Unit, Kyushu University, Fukuoka, Japan) for the assistance, and Mr N. J. Halewood (a native English speaker) for the review.

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Masafumi Sanefuji, MD
Shouichi Ohga, MD
Ryutaro Kira, MD
Department of Pediatrics
Graduate School of Medical Sciences
Kyushu University

Brief Communications

Takashi Yoshiura, MD
Department of Radiology
Graduate School of Medical Sciences
Kyushu University
Hiroyuki Torisu, MD
Toshiro Hara, MD
Department of Pediatrics
Graduate School of Medical Sciences
Kyushu University
Fukuoka, Japan
Received December 27, 2004. Received revised February 22, 2005. Accepted
for publication February 23, 2005.
This work was supported in part by a Grant-in-Aid for Scientific Research
to Dr Ohga from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
Address correspondence to Dr Masafumi Sanefuji, Department of Pediatrics,
Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka
812-8582, Japan. Tel: +81-92-642-5421; fax: +81-92-642-5435;
e-mail: sane26@pediatr.med.kyushu-u.ac.jp.
DOI 10.2310/7010.2006.00006

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Matsushima Y, Aoyagi M, Nariai T, et al: Long-term intelligence outcome of post-encephalo-duro-arteri-synangiosis in childhood moyamoya patients. Clin Neurol Neurosurg 1997;99(Suppl 2):S147–S150.

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Olivieri NF: The beta-thalassemias. N Engl J Med 1999;341:99–109.

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Eldor A, Durst R, Hy-Am E, et al: A chronic hypercoagulable state in
patients with beta-thalassaemia major is already present in childhood. Br J Haematol 1999;107:739–746.

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Eldor A, Rachmilewitz EA: The hypercoagulable state in thalassemia.
Blood 2002;99:36–43.

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1998;91:288–294.

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Ganesan V, Prengler M, McShane MA, et al: Investigation of risk factors
in children with arterial ischemic stroke. Ann Neurol 2003;53:167–173.

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Mukherjee A: Moyamoya disease and ␤-thalassemia. J Assoc Physicians India 1995;43:710–711.

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Chifu Y, Nakashima H, Hara T, et al: Beta-thalassemia major resulting
from a compound heterozygosity for the beta-globin gene mutation:
Further evidence for multiple origin and migration of the thalassemia
gene. Hum Genet 1992;89:343–346.

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Suzuki J, Takaku A: Cerebrovascular “moyamoya” disease: Disease
showing abnormal net-like vessels in base of brain. Arch Neurol
1969;20:288–299.

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Pegelow CH: Stroke in children with sickle cell anaemia: Aetiology and
treatment. Paediatr Drugs 2001;3:421–432.

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Grotta JC, Manner C, Pettigrew LC, Yatsu FM: Red blood cell disorders and stroke. Stroke 1986;17:811–817.

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Stockman JA, Nigro MA, Mishkin MM, Oski FA: Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med 1972;287:846–849.

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Tokunaga Y, Ohga S, Suita S, et al: Moyamoya syndrome with spherocytosis: Effect of splenectomy on strokes. Pediatr Neurol
2001;25:75–77.

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Cohen N, Berant M, Simon J: Moyamoya and Fanconi’s anemia. Pediatrics 1980;65:804–805.

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Butrum MW, Williams LS, Golomb MR: A child with Diamond-Blackfan
anemia, methylenetetrahydrofolate reductase mutation, and perinatal stroke. J Child Neurol 2003;18:800–802.

17.

Kaysser TM, Wandersee NJ, Bronson RT, Barker JE: Thrombosis and
secondary hemochromatosis play major roles in the pathogenesis of
jaundiced and spherocytic mice, murine models for hereditary spherocytosis. Blood 1997;90:4610–4619.

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Peerless SJ: Risk factors of moyamoya disease in Canada and the USA.
Clin Neurol Neurosurg 1997;99(Suppl 2):S45–S48.

77

A Boy With Muscle Weakness, Hypercarbia, and the
Mitochondrial DNA A3243G Mutation
ABSTRACT
The point mutation in the mitochondrial genome tRNALeu (A3243G)
is associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). We
report a boy presenting with respiratory compromise and hypercarbia owing to severe muscle weakness. Historically, he demonstrated idiopathic growth hormone deficiency, retarded bone age,
and exercise avoidance. Owing to severe respiratory compromise
out of proportion to expected recovery, a metabolic work-up was
performed. Muscle biopsy demonstrated abnormal mitochondria
structure and heteroplasmic A3243G mutation. Idiopathic growth
hormone deficiency and retarded bone age have not been previously reported in MELAS, and these findings delayed testing for
mitochondrial disease. This case demonstrates that isolated muscle weakness in the context of other organ system abnormalities
should make the investigator consider MELAS. (J Child Neurol
2006;21:77–79).

The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and
strokelike episodes (MELAS) is a well-defined mitochondrial encephalomyopathic syndrome.1 This syndrome is genetically heterogeneous, with various point mutations in mitochondrial transfer ribonucleic acid and electron
transport chain complexes.2–5 The A3243G mutation accounts for 80% of the
mutations identified in MELAS, with other abnormalities accounting for the
remainder. Owing to threshold and heteroplasmy, the A3243G tRNALeu for
leucine mutation can present with distinctive features not usually associated with classic MELAS.1,6 We report the unique presentation of a child presenting with severe muscle weakness–induced hypercarbia, without the other
cardinal features of MELAS, with the A3243G mutation. Retrospectively, this
case suggests that retarded bone maturation and idiopathic growth hormone
deficiency might be associated with the A3243G mutation.

Case Report
Our patient, an 11-year-old boy, presented with a 2-week history of upper
respiratory symptoms. Prior to illness, he was an honor student and competitive chess player. He disliked physical sports and did not participate in
physical education classes. His short stature and delayed bone maturation
were thought to be due to isolated idiopathic growth hormone deficiency.
Otherwise, his medical history was unrevealing for abnormalities. Respiratory difficulties began with an upper respiratory illness. On hospitalization, the initial examination showed a severely hypotonic boy with shallow
respirations, hypnic breathing, and metabolic acidosis. His condition deteriorated, with arterial blood gases showing carbon dioxide partial pressure
levels in the 70s, in the context of an upper respiratory illness. Owing to carbon dioxide partial pressure levels and breathing pattern, he was subsequently tracheally intubated with mechanical ventilation for 7 days.
Echocardiography demonstrated diffuse mild cardiomyopathy. Blood work
revealed severe lactic acidosis. The etiology of the respiratory illness was
not found. Magnetic resonance imaging of the brain was interpreted as without abnormality. He underwent muscle biopsy, with subsequent analysis of
mitochondrial electron transport chain complex enzymatic activity, electron
microscopy, histologic analysis, and mitochondrial DNA testing. Before
hospital discharge, a sleep study revealed obstructive sleep apnea with nighttime elevated carbon dioxide partial pressure levels, 85 to 124 mm Hg.
After several months, repeat cardiac echocardiography revealed a normal
functioning heart without cardiomyopathy. He was weaned off nighttime
continuous positive airway pressure, with normalized carbon dioxide par-

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