The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.
"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."
Abnormal Response to Injury
Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.
A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.
A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.
Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.
Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.
Accumulation of Abnormal Metabolites
The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.
The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.
The authors had no financial conflicts to report.