Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.
Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).
Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.
To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.
Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).
Abnormalities in Vascular Development
The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.
ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.
Abnormal Vascular Homeostasis and Remodeling
The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.
NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.
The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.
Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.
Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.
Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.