Lunliya Thampratankul1, Yusuke Okuno2, Patcharee Komvilaisak3, Duangrurdee Wattanasirichaigoon1 and Nongnuch Sirachainan1.
1 Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
2 Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
3 Department of Pediatrics, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Professor Nongnuch Sirachainan, MD, Department of Pediatrics Faculty of
Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400
Thailand. Tel: +66 2 201 1749. Fax: +66 2 201 1748. E-mail: email@example.com
Published: July 1, 2022
Received: March 31, 2022
Accepted: June 18, 2022
Mediterr J Hematol Infect Dis 2022, 14(1): e2022057 DOI 10.4084/MJHID.2022.057
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
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medium, provided the original work is properly cited.
To the editor
is an occlusive vasculopathy characterized by progressive bilateral or
unilateral stenosis/occlusion of the distal internal carotid artery and
the abnormal development of a hazy network of basal collateral
vessels.1 Moyamoya, classified into moyamoya syndrome and moyamoya
disease, is more common in Asian than in Western countries. Moyamoya
syndrome is associated with underlying conditions, such as
hemoglobinopathy and post-radiation, while moyamoya disease is not. The etiology of moyamoya remains unknown; however, genetic analyses identified the variable incidence rates of RNF213 p.R4810K of 23.1-90.1% in most East Asian populations.
The genetic variants of moyamoya reported from Southeast Asian
countries are limited. Therefore, we reported the underlying disease of
non-deletional α-thalassemia, antiphospholipid antibodies (APAs), and
genetic variants of PROC p.R189W, and less frequent RNF213 p.R4810K in moyamoya disease/syndrome, using whole-exome sequencing (WES).
describe a cross-sectional study involving 14 patients (7 with moyamoya
syndrome and 7 with moyamoya disease), female: male 1.33:1, with a
median age of 9.3 years (1.7-12.6) at diagnosis. Their median follow-up
time was 6.3 years. The diagnosis was confirmed using magnetic
resonance imaging and angiographic study. Recurrent hemiparesis and
seizure were the most common presentations. All patients had no family
history of moyamoya. Genomic DNA was extracted from peripheral blood
samples and sent for WES, performed on a Novaseq 6000 System (Illumina,
San Diego, CA, USA). WES data were analyzed using the commercial
software, Sophia DDM, V4.4 (Sophia Genetics). This study was approved
by the Ethics Committee of the Faculty of Medicine Ramathibodi Hospital
(ID: COA. MURA2020/1788).
Among the seven
patients with moyamoya syndrome, three were diagnosed with
non-deletional α-thalassemia disease [hemoglobin H/Constant Spring
(--SEA/CS)], one with Williams syndrome, and one post cranial
radiation. Two of the three α-thalassemia patients also had APAs. The
WES study demonstrated a heterozygous variant of a prothrombotic gene
of heterozygous PROC gene
mutation (c.565C > T, p.R189W) in three patients. Two patients had
low protein (PC) activities (42% and 61%). WES study also confirmed the
genetic information of thalassemia [αCS (HBA2: c.427T > C)/ --SEA
(NG_000006.1: g.26264_45564del19301)] among three patients. One of the
three heterozygous p.R189W mutation patients also had homozygous HBB
c.79G>A, p.E27K, causing mild anemia (Table 1 and Supplement Figure 1). For the seven patients with moyamoya disease, the WES study identified genetic variants of heterozygous RNF213 mutation (c.14429G>A, p.R4810K) in two patients (Table 1 and Supplement Figure 1).
||Table 1. Characteristics
of the 14 patients with moyamoya. Patients 1-7 were classified as
moyamoya syndrome, and Patients 8-14 as moyamoya disease.
outcomes revealed neurologic deficits among seven patients. The
modified Rankin scale (mRS) was higher in moyamoya syndrome (score 3 in
craniopharyngioma post cranial radiation, score 2 in alpha thalassemia
disease, and score 1 in Williams syndrome), indicating higher
disability when compared with moyamoya disease (score 1 in two of seven
Sickle cell anemia and β thalassemia had been reported in moyamoya syndrome.
The present study reported non-deletional α-thalassemia in moyamoya.
The α-thalassemia disease usually involves moderate anemia and requires
occasional red blood cell (RBC) transfusion. However, non-deletional
α-thalassemia may exhibit more severe phenotypes, similar to patients
with ꞵ-thalassemia. The patients in this report,
before the diagnosis of moyamoya, received occasional RBC transfusions.
As a result, the high proportion of phosphatidylserine exposing RBC
increased the hypercoagulable state and may
contribute to the developing moyamoya. The additional prothrombotic
risk factors were APAs in two α-thalassemia patients and PROC
p.R189W in one patient. The p.R189W mutation, resulted in low or
slightly low levels of PC activity. The related report suggested that
p.R189W had a low binding affinity to endothelial PC receptors;
however, some patients with p.R189W had normal PC activity.[5,6] WES demonstrated the prothrombotic genetic variants of the PROC
p.R189W mutation in three patients. These findings indicated the
overall prothrombotic risk factors in 35.7% of patients and 71.4% of
moyamoya syndrome, including two patients with APS and three with PROC
p.R189W mutation. A related study reported prothrombotic risk factors
consisting of APAs and PS deficiencies in 40% of the investigated ten
In addition to prothrombotic risk
factors, one patient in this study presented Williams syndrome
associated with vascular abnormality, including peripheral pulmonary
stenosis and moyamoya syndrome. One patient
developed moyamoya syndrome after 18 months of 54 Gy cranial radiation.
Altogether, 14.2% of our reported patients and 28.6% of moyamoya
disease demonstrated RNF213
p.R4810K, which was lower than that reported among Japanese (90.1%) and
Korean (78.9%). Still, the same as in Chinese (23.2%) patients. The incidence was higher than the prevalence in the general population (0-11.4%). The RNF213
gene, located on chromosome 17q25.3, is related to angiogenesis and
vascular inflammation with an unknown physiologic function.
the number of enrolled patients was small due to the rarity of the
disease, our report demonstrated a non-deletional type α-thalassemia
disease (--SEA/ α^csα), and APAs in moyamoya syndrome. In addition to
the prothrombotic risk factor of genetic variants of PROC p.R189W. Moreover, the (RNF213 p.R4810K was identified in 28.6% of moyamoya disease. In addition, the RNF213 p.R4810K was identified in 28.6% of moyamoya disease.
thank Dr. Chaiyos Khongkhatithum MD, Thipwimol Tim-Aroon MD, Duantida
Songdej MD, and Pongpak Pongphitcha MD for their advice and
contribution to the research. We thank the patients and their families,
and all medical personnel involved in providing care to the patients.
This research project is supported by the Faculty of Medicine
Ramathibodi Hospital Mahidol University (Grant ID CF_63003).
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||Supplement Figure 1. Sequencing results of: (A), RNF213 c.14429G>A, p.R4810K in patients 11 and 13; and (B), PROC c.565C>T, p.R189W in patients 5, 7, and 9. Diagram (C) demonstrates the possible pathogeneses of moyamoya from this report, including genetic variants of RNF213 p.R4810K resulting in abnormal angiogenesis; PROC p.R189W
resulting in increased thrombus formation, and contributing factors
such as infection, inflammation, thalassemia disease, neurofibromatosis
type I, cranial radiation and Williams syndrome.