Genetics of Pediatric Arteriopathies Could Inform Stroke Treatment

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.

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.

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.

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.

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.

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.