Last updated:
02/09/2023
Years published: 1989, 1996, 2003, 2004, 2007, 2009, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Edward R. Smith, MD, Department of Neurosurgery, Children’s Hospital Boston/Harvard Medical School, and R. Michael Scott, MD, Neurosurgeon-in-Chief-emeritus, Children’s Hospital Boston, for assistance in the preparation of this report.
Moyamoya disease is a progressive disorder that affects the blood vessels in the brain (cerebrovascular). It is characterized by the narrowing (stenosis) and/or closing (occlusion) of the carotid artery inside the skull, a major artery that delivers blood to the brain. At the same time, tiny blood vessels at the base of the brain open up in an apparent attempt to supply blood to the brain distal to the blockage. These tiny vessels are the “moyamoya” vessels for which the disease was named. Inadequate blood supply then leads to reduced oxygen delivery to the brain, and it is this oxygen deprivation that causes the signs of moyamoya. One of the symptoms is typically stroke, which results in paralysis of the face, arms or legs, loss of speech, etc., or temporary loss of neurologic function of body parts or speech (transient ischemic attacks, or “TIA”). Other symptoms that may result include headaches, visual disturbances, developmental delay, and seizures. Approximately 10-30% of cases of moyamoya in Asian countries have a genetic cause. Patients with this arteriopathy that occurs either on a familial or idiopathic basis are said to have moyamoya disease. Patients in whom the artery changes occur in association with another process such as sickle cell disease or Down syndrome are said to have moyamoya syndrome, but in this report, we use the term “moyamoya disease” as shorthand for both forms.
Although moyamoya disease may occur at any age, there are two peak incidence periods –between the ages of five and ten years in children, and between 30 to 50 years in adults. Children with moyamoya disease may present with a variety of symptoms, but most present with those related to reduced brain blood supply, including stroke, transient ischemic attacks (TIAs), headaches, seizures, involuntary movements or occasionally progressive developmental delay.
Although adults with moyamoya also present with signs and symptoms of brain ischemia, they also have a greater tendency to suffer intracranial hemorrhage than children, presumably due to rupture of the tiny moyamoya blood vessels possibly in the setting of higher blood pressures seen in adulthood.
The exact causes of moyamoya disease are still not completely known, but genetics seem to play an important role. About 12% of people with moyamoya disease have other family members with the condition. In Japan, about 10% of patients have a close relative with the disease, compared with about 6% in the United States.
Researchers believe the disease is usually inherited in an autosomal dominant pattern. This means that a child only needs to inherit one changed copy of the gene from a parent to possibly develop the disease. However, the disease also shows incomplete penetrance, meaning that some people who carry the gene change never develop symptoms.
Studies of large Japanese families with many affected members found that the disease is more often passed down from the mother. These studies also showed that affected mothers are more likely to have daughters with the disease. This suggests that epigenetic changes may play a role. Epigenetics refers to changes in how genes are turned on or off without changing the genes themselves. One possible example is genomic imprinting, where the effect of a gene depends on whether it is inherited from the mother or the father.
Researchers have found that the RNF213 gene is the main gene linked to moyamoya disease. A gene is a section of DNA that contains instructions for how the body works. One specific change in this gene, called the R4810K variant, is especially common in East Asian populations. A variant is a change in the DNA sequence of a gene. This variant is found in about 80–90% of inherited moyamoya cases in Japan and South Korea, and about 20–30% of inherited cases in China.
However, many people who carry this gene change never develop the disease. About 1.5% of healthy people in Japan and South Korea carry the variant without symptoms. This is because the variant has low penetrance, meaning that having the gene change does not always lead to disease. For people who inherit one copy of the variant from one parent, the risk of developing moyamoya disease is only about 1 in 150. These people are called heterozygous carriers, meaning they have one altered copy of the gene and one normal copy. People who inherit two altered copies, one from each parent, are called homozygous carriers, and their risk is much higher, with more than 78% developing the disease.
The RNF213 gene helps regulate how blood vessels in the brain grow and repair themselves. It works in a process called angiogenesis, which means the formation of new blood vessels, and in vascular remodeling, which refers to changes in the structure of blood vessels over time. Most harmful RNF213 variants are missense variants, meaning a small DNA change causes one building block of the protein to be replaced with another. These changes may either make the protein work abnormally or interfere with the normal protein’s function.
In White populations, the R4810K variant is extremely rare, but other uncommon RNF213 variants have also been linked to moyamoya disease. This suggests that RNF213 increases susceptibility, or risk, for moyamoya disease in many different populations, although the exact gene changes vary by ancestry.
Scientists have also identified several other genes associated with moyamoya disease. Changes in the ACTA2 gene are linked to a distinct form of the disease that also affects smooth muscle cells in blood vessels, including those in the heart and aorta, the body’s largest artery. Variants in the DIAPH1 gene can disrupt the structure and movement of cells in blood vessel walls. This happens because the gene affects actin remodeling, which is the process cells use to change shape and maintain their internal structure.
Variants in the GUCY1A3 gene affect how blood vessel muscle cells respond to nitric oxide, a natural chemical that helps blood vessels relax and adapt to changes in blood flow. Variants in the ANO1 gene affect a protein channel involved in calcium movement within cells. Calcium signaling helps regulate many cell functions, including muscle contraction and blood vessel activity. Certain ANO1 variants have been associated with typical moyamoya disease features and involvement of blood vessels in the back part of the brain.
Overall, researchers have linked at least 16 genes and several biological pathways to moyamoya disease. A biological pathway is a series of processes inside cells that work together to control functions in the body. These pathways include inflammation, DNA repair, blood clotting, cell communication, and blood vessel development. Despite these discoveries, known genetic changes explain less than 2% of all moyamoya cases, and many patients still do not have an identifiable genetic cause, especially in European populations.
Both genetic and environmental factors appear to contribute to the disease. Evidence for this comes from reports of identical twins in which only one twin develops moyamoya disease. Since identical twins share the same DNA, this suggests that outside influences may help trigger the condition in people who are already genetically susceptible.
Known non-genetic risk factors include autoimmune diseases, which are conditions where the immune system mistakenly attacks the body’s own tissues, as well as radiation exposure and infections. Because many moyamoya-related gene variants have low penetrance and differ between populations, genetic testing currently has limited value for diagnosis and genetic counseling.
In Japan, moyamoya disease typically occurs in females under the age of 20. In Japan, the disease is estimated to occur in 1 per 300,000 people. Although moyamoya was originally reported in individuals of Japanese ancestry, cases have been reported from elsewhere in Asia as well as from Europe, North and South America and most series reported in the western hemisphere have a minority of patients of Asian descent. Of note, most patients in North America are isolated cases, with recent literature suggesting that less than 4% of cases in this population are familial. (Gaillard 2017)
In most patients, the diagnosis of moyamoya can be made from a careful assessment of an MRI and MRA.
An MRI/MRA scan using a magnet strength of at least 1.5 Tesla (1.5T) can usually confirm the diagnosis of moyamoya disease.
An MRI (magnetic resonance imaging) uses strong magnets and radio waves to create detailed images of the brain and surrounding tissues. It helps doctors detect strokes, brain damage, or changes caused by reduced blood flow.
An MRA (magnetic resonance angiography) is a special type of MRI that focuses specifically on blood vessels. It allows doctors to see narrowing or blockage of the brain’s arteries and the formation of the small abnormal collateral vessels that are characteristic of moyamoya disease.
Cerebral arteriography can also confirm the diagnosis, establish the exact degree of blood vessel narrowing, demonstrate the existing blood flow patterns to various areas of the brain, and allow treatment decisions to be made; Current guidelines allow a definitive diagnosis by MRI/MRA (≥1.5 Tesla) without catheter angiography.
However, catheter angiography remains valuable for surgical planning, particularly, catheter angiography can help with the identification of important blood vessels called “transdural collaterals,” which are present in some cases and can markedly influence surgical planning and prognosis. (Storey 2017)
No medication can stop the progressive narrowing of the brain arteries in moyamoya disease, and most affected people continue to worsen with medical therapy alone. Surgical revascularization, which restores blood flow to the brain, is the definitive treatment for symptomatic moyamoya disease.
Aspirin is commonly used to reduce the risk of blood clots in narrowed vessels and may improve bypass patency after surgery without increasing bleeding risk. Cilostazol, an antiplatelet medication with blood vessel–widening effects, may provide greater survival benefit than other antiplatelet medications, although further studies are needed. Anti-seizure medications are used when appropriate. Long-term anticoagulants such as warfarin are generally avoided because of the risk of brain hemorrhage.
Headaches are common in moyamoya disease. Migraine medications that narrow blood vessels, reduce blood vessel dilation, or lower blood pressure too much should generally be avoided because they may worsen reduced brain blood flow. Maintaining hydration, stable blood pressure, and avoiding anemia are important for stroke prevention.
Surgical revascularization restores blood supply to the brain by redirecting scalp blood vessels to the brain surface. The AHA/American Stroke Association recommends surgical revascularization for symptomatic patients. Procedures include direct bypass, which immediately connects a scalp artery to a brain artery; indirect bypass, which stimulates new blood vessel growth over time; and combined bypass, which uses both techniques.
The Japan Adult Moyamoya Trial showed that direct bypass surgery significantly reduced recurrent bleeding compared with conservative treatment in hemorrhagic moyamoya disease. Although no randomized trials have evaluated surgery specifically for ischemic stroke prevention, multiple studies and meta-analyses support the benefit of revascularization, including in children.
Long-term surgical outcomes are generally favorable, with low stroke rates and good functional recovery in most patients. In children, surgery reduces stroke risk from as high as 90% without treatment to less than 5% after revascularization.
Endovascular procedures such as angioplasty and stenting are not recommended because of low success rates and high complication risks. Treatment at experienced high-volume centers is strongly associated with better outcomes. Genetic counseling may be helpful for families with hereditary moyamoya disease.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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For information about clinical trials sponsored by private sources, contact:
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For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
Scott RM. Moyamoya Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:559.
Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2342.
Bennett JC, Plum F. Eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:888.
Behrman RE, Kliegman RM, Arvin AM. Eds. Nelson Textbook of Pediatrics. 15th ed. W.B. Saunders Company. Philadelphia, PA; 1996:1729.
REVIEW ARTICLES
Ferriero DM, Fullerton HJ, Bernard TJ, et al. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke. 2019;50(3):e51-e96. doi:10.1161/STR.0000000000000183
Riordan CP, Storey A, Cote DJ, Smith ER, Scott RM. Results of more than 20 years of follow-up in pediatric patients with moyamoya disease undergoing pial synangiosis [published online ahead of print, 2019 Mar 1]. J Neurosurg Pediatr. 2019;1-7. doi:10.3171/2019.1.PEDS18457
See P, Ropper AE, Underberg DL, Robertson RL, Scott RM, Smith ER, Down syndrome and moyamoya: clinical presentation and surgical management. J Neurosurg Pediatr. 2015;Jul;16(1):58-63.
Scott RM, Smith ER. Medical progress: moyamoya disease and moyamoya syndrome. NEJM. 2009; Mar;360 (12):1126-37
Smith ER, Scott RM, Progression of disease in unilateral moyamoya syndrome. Neurosurg Focus 2008;24(2):E17.
JOURNAL ARTICLES
Gaillard J et al. Incidence, clinical features, and treatment of familial moyamoya in pediatric patients: a single-institution series. J Neurosurg Pediatr. 2017;19(5):553-559.
Storey A, et al. Preoperative transdural collateral vessels in moyamoya as radiographic biomarkers of disease. J Neurosurg Pediatr. 2017;19(3):289-295.
Titsworth WL., Scott RM, and Smith ER. National analysis of 2454 pediatric moyamoya admissions and the effect of hospital volume on outcomes. Stroke 2016;47(5):1303-11.
Munot P, Saunders DE, Milewicz DM, et al. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain 2012 135(Pt 8):2506–14.
Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first Moya-moya disease gene. J Hum Genet. 2011;56: 34–40.
Morioka M, Hamada J, Todaka T, et al. High-risk age for rebleeding in patients with hemorrhagic Moyamoya disease: long-term follow-up study. Neurosurgery 2003;52:1049-55.
Oya S, Tsutsumi K, Ueki K. Adult-onset moyamoya disease with repetitive ischemic attacks successfully treated by superficial temporal-middle cerebral artery by-pass: case report. Neurol Med Chir (Tokyo). 2003;43:138-41.
Marioka M, Hamada J, KawanoT, et al. Angiographic dilatation and branch extension of the anterior choroidal and posterior communicating arteries are predictive of hemorrhage in adult moyamoya patients. Stroke 2003;34:90-95.
Zafeiriou DI, et al. Familial moyamoya disease in a Greek family. Brain Dev. 2003;25:288-90.
Asumal KB, et al. Moyamoya disease: an elusive diagnosis. J Pak Med Assoc. 2003;53:160-2.
Scott RM, Smith JL, Robertson RL, Madsen JR, Soriano SG, Rockoff MA. Long-term outcome in children with moyamoya syndrome after cranial revascularization by pial synangiosis. J Neurosurg: Pediatrics 2004; 100: 142-149.
Dobson SR, Holden KR, Nietert PJ, et al. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood 2002;99:3144-50.
Soriano SG, Cowan DB, Proctor MR, et al. Levels of soluble adhesion molecules are elevated in the cerebrospinal fluid of children with moyamoya syndrome. Neurosurgery 2002;50:54-49.
Isono M, Ishii K, Kamida T, et al. Long-term outcomes of pediatric moyamoya disease treated by encephalo-duro-arterio-synangiosis. Pediatr Neurosurg. 2002;36:14-21.
Gonzalez NR, Amin-Hanjani S, Bang OY, et al. Adult moyamoya disease and syndrome: current perspectives and future directions: a scientific statement from the American Heart Association/American Stroke Association. Stroke. 2023;54(10):e465-e479. doi:10.1161/STR.0000000000000443.
Rifino N, Aamodt AH, Wiedmann M, et al. The spectrum of headaches in moyamoya angiopathy: from mechanisms to management strategies: a consensus review from the NEUROVASC Working Group. Eur J Neurol. 2025;32(10):e70316. doi:10.1111/ene.70316.
Ihara M, Yamamoto Y, Hattori Y, et al. Moyamoya disease: diagnosis and interventions. Lancet Neurol. 2022;21(8):747-758. doi:10.1016/S1474-4422(22)00165-X.
Takahashi JC, Funaki T, Houkin K, et al. Impact of cortical hemodynamic failure on both subsequent hemorrhagic stroke and effect of bypass surgery in hemorrhagic moyamoya disease: a supplementary analysis of the Japan Adult Moyamoya Trial. J Neurosurg. 2021;134(3):940-945. doi:10.3171/2020.1.JNS192392.
Shahbandi A, Sattari SA, Azad TD, et al. The management of symptomatic moyamoya disease in pediatric patients: a systematic review and meta-analysis. Neurosurgery. 2024;97(1):65-81. doi:10.1227/neu.0000000000003277.
Teo M, Abhinav K, Bell-Stephens TE, et al. Short- and long-term outcomes of moyamoya patients post-revascularization. J Neurosurg. 2023;138(5):1374-1384. doi:10.3171/2022.8.JNS22336.
INTERNET
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Moyamoya Disease. Entry Number; 252350: Last Edit Date 09/08/21.Available at: https://omim.org/entry/252350 Accessed Dec 7, 2022.
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Moyamoya Disease 2. Entry Number; 607151: Last Edit Date09/29/21. Available at: https://omim.org/entry/607151 Accessed Dec 7, 2022.
NINDS Moyamoya Disease Information Page. Date last modified:Jul 25, 2022. https://www.ninds.nih.gov/Disorders/All-Disorders/Moyamoya-Disease-Information-Page Accessed Dec 7, 2022.
Sucholeiki R, Chawla J. Moyamoya Disease.Medscape.Updated: Nov 9, 2018. www.emedicine.com/neuro/topic616.htm Accessed Dec 7, 2022.
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