Knowledge on rare diseases and orphan drugs

The incidence of MMD is highest in Asian populations but MMD occurs in many other ethnic groups. The incidence ranges from 1/280,000 to 1/89,000 in Japan and China to1/1,100,000 in the US. The prevalence in Japan is estimated to be 1/30,000-1/9,500.

There are two peak incidence ages: young children (5-9 years) and adults (mid-40s). Involvement is usually bilateral but unilateral cases are reported. Disease manifestations are highly variable. Some affected individuals remain asymptomatic, some develop transient attacks, and others severe neurologic deficits as a result of infarcts or hemorrhage. Hemorrhage occurs less often in children. Other manifestations include headache, dizziness, seizures, and chorea. Some patients present intellectual disability. The course is also highly variable but generally progressive. The term MMD is used when there is no cause and Moyamoya syndrome (MMS) when the disease is associated with other diseases (sickle cell anemia, neurofibromatosis).

The etiology of MMD is not currently known but is thought to be multifactorial with genetic determinants playing a role. In Japan, about 15% of patients have a family history. Mutations in the RNF213(17q25.3) gene have been found in some patients but their pathogenic role remains unclear. The intracranial vasculopathy associated with smooth muscle actin alpha 2 (ACTA2) (10q23.31) mutations has been referred to as MMS, but it has distinctive angiographic features, including dilatation of proximal ICAs, an abnormally straight course of intracranial arteries, and absence of typical moyamoya collateral vessels.

The diagnosis of MMD may be difficult because it is rare and because of the non-characteristic signs and symptoms. Diagnosis is suspected on the basis of the clinical presentation and imaging findings. Cerebral angiography is the standard confirmatory diagnostic method. Moyamoya disease involves in particular the supraclinoid internal carotid arteries and their proximal branches. The term moyamoya means "puff of smoke" in Japanese, in reference to the appearance of abnormal vascular collateral networks on angiography that develop adjacent to the stenotic vessels. Magnetic resonance angiography (MRA) can also be used.

MMD may develop in an isolated manner but can also be associated with other diseases when it is known as MMS: typical angiographic MMDfeatures associated with other diseases, e.g. sickle cell anemia, Down syndrome, neurofibromatosis type 1 and many others.

Autosomal dominant inheritance with incomplete penetrance has been described in affected Japanese families. Other suggested patterns include autosomal-recessive, X-linked-recessive, or multifactorial inheritance.

No specific treatment to stop progression or reverse the intracranial arteriopathy is available for MMD. Drug therapy is mainly used to counter disease complications such as stroke and transient ischemic attacks, to alleviate symptoms, and to prevent cognitive deterioration. Physical, occupational and speech therapy may be needed after attacks. Surgical revascularization procedures to restore blood flow to the brain involving direct, indirect or combined techniques have also been used and appear to reduce the risk ofischemic stroke and possibly cognitive dysfunction. The indication and timing of surgery remains controversial.

Early detection and appropriate treatment improve the long-term outcome. The prognosis depends on disease severity. Mortality rates are estimated at about 5% for adults and 2% for children. The main cause of death is hemorrhage.

Last update: April 2015 - Expert reviewer(s): Dr Karin KLIJN