Moyamoya disease is a rare, progressive cerebrovascular disorder caused by blocked arteries at the base of the brain in an area called the basal ganglia. Moyamoya means “puff of smoke” in Japanese and is used to describe the tangled appearance of tiny vessels compensating for the blockage.  

Moyamoya disease was first described in Japan and is found in individuals around the world, although its incidence is higher in Asian countries than in Europe or North America. The disease primarily affects children, but can also occur in adults.

In children, the first symptom of moyamoya disease is often stroke or recurrent transient ischemic attacks (TIAs), also known as “mini-strokes," that are frequently accompanied by muscular weakness or paralysis affecting one side of the body. Adults may also experience these symptoms that arise from blocked arteries, but more often experience a hemorrhagic stroke due to bleeding into the brain. Other symptoms may include:

• Headaches
• Seizures
• Disturbed consciousness
• Involuntary movements
• Vision problems
• Cognitive and/or sensory impairment

Some individuals have a close relative who is also affected; in these cases, researchers think the disease is the result of inherited genetic abnormalities.

Medications may be prescribed to reduce the risk of stroke. Several types of surgery can restore blood flow (revascularization) to the brain by opening narrowed blood vessels or by bypassing blocked arteries. Some individuals have no further strokes or related problems after surgery.

Without surgery, the majority of individuals with moyamoya disease will experience mental decline and multiple strokes because of the progressive narrowing of arteries. Without treatment, moyamoya disease can be fatal as the result of intracerebral hemorrhage (bleeding within the brain).

Moyamoya disease was first identified in Japan, where it is most prevalent, affecting about 5 in 100,000 individuals. The condition is also relatively common in other Asian populations. It is ten times less common in Europe. In the United States, Asian Americans are four times more commonly affected than whites. For unknown reasons, moyamoya disease occurs twice as often in females as in males.

The genetics of moyamoya disease are not well understood. Research suggests that the condition can be passed through families, and changes in one gene, RNF213, have been associated with the condition. Other genes that have not been identified may be involved in moyamoya disease. It is also likely that other factors (such as infection or inflammation) in combination with genetic factors play a role in the condition's development.

The RNF213 gene provides instructions for making a protein whose function is unknown. However, research suggests that the RNF213 protein is involved in the proper development of blood vessels.

Changes in the RNF213 gene involved in moyamoya disease replace single protein building blocks (amino acids) in the RNF213 protein. The effect of these changes on the function of the RNF213 protein is unknown, and researchers are unsure how the changes contribute to the narrowing of blood vessels or the characteristic blood vessel growth of moyamoya disease. For unknown reasons, people with moyamoya disease have elevated levels of proteins involved in cell and tissue growth, including the growth of blood vessels (angiogenesis). An excess of these proteins could account for the growth of new blood vessels characteristic of moyamoya disease. It is not clear if changes in the RNF213 gene are involved in the overproduction of these proteins.

Normal Function

The RNF213 gene provides instructions for making a protein whose role is unknown. The RNF213 protein, which is found in tissues throughout the body, contains specific regions (domains) that hint at possible functions. One domain, known as a RING finger, is found in proteins that have an enzyme activity known as E3 ubiquitin-protein ligase. Proteins with this activity target other proteins to be broken down (degraded) within cells. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells. Proteins with a RING finger domain are involved in many different cellular functions, including cell growth and division, the transmission of chemical signals (signal transduction), and the self-destruction of cells (apoptosis).

The RNF213 protein also contains two regions called AAA+ ATPase domains. Proteins with these domains typically regulate mechanical processes in the cell, such as protein unfolding, DNA unwinding, or transporting molecules.

Although the function of the RNF213 protein is unknown, studies suggest that it plays a role in the proper development of blood vessels.

Health Conditions Related to Genetic Changes

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Moyamoya disease

At least 24 genetic changes in the RNF213 gene have been associated with moyamoya disease. This condition is characterized by narrowing of blood vessels in the brain and subsequent growth of networks of small, fragile blood vessels. The resulting lack of blood flow in the brain leads to strokes and other features of the condition.

Changes in the RNF213 gene involved in moyamoya disease replace single protein building blocks (amino acids) in the RNF213 protein. The most common change is a normal variation (polymorphism) of the gene that replaces the amino acid arginine with the amino acid lysine at protein position 4810 (written as Arg4810Lys or R4810K). This genetic change is found in a majority of affected individuals in Asian populations and is relatively common in unaffected individuals in these populations, occurring in about 1 percent. (This phenomenon, in which people with an altered copy of the gene never develop the condition, is known as reduced penetrance.) However, the Arg4810Lys change is not found in affected individuals of European descent. These individuals have rarer RNF213 gene mutations that change single amino acids in the protein.

Little is known about the effect of these changes on the function of the RNF213 protein, and researchers are unsure how the changes contribute to the characteristic blood vessel abnormalities of moyamoya disease. It is unclear if RNF213 gene mutations are involved in the narrowing of blood vessels in the brain. For unknown reasons, people with moyamoya disease have elevated levels of proteins involved in cell and tissue growth, including the growth of blood vessels (angiogenesis). An excess of these proteins could account for the growth of new blood vessels characteristic of moyamoya disease. It is not clear if changes in the RNF213 gene are involved in the overproduction of these proteins.

Little is known about the cause of moyamoya disease. Studies suggest that other genes could be involved in development of the condition. It has been suggested that other factors, such as infection or inflammation, in combination with genetic changes may be necessary for development of moyamoya disease.

Other Names for This Gene

• ALK lymphoma oligomerization partner on chromosome 17
• ALO17
• C17orf27
• E3 ubiquitin-protein ligase RNF213
• KIAA1554
• KIAA1618
• MYMY2
• mysterin
• MYSTR
• NET57
• RN213_HUMAN

Genomic Location

Up to 15 percent of Japanese people with moyamoya disease have one or more family members with the condition, indicating that the condition can be passed through generations in families; however, the inheritance pattern is unknown. Research suggests that the condition follows an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. However, some people who have a copy of the altered gene never develop the condition, which is a situation known as reduced penetrance.

Moyamoya disease is progressive and without treatment can be fatal due to intracerebral hemorrhage. Without surgery, the majority of affected people experience recurrent strokes and gradual deterioration of cognitive function. In studies with long-term follow-up of untreated patients, progressive neurologic deficits and poor outcome were reported in 50 to 66 percent.

The overall mortality rate from Moyamoya disease is about 10% in adults, and 4.3% in children.