Cerebrovascular Disease Genetics

Several cerebrovascular disorders tend to run in families or are either entirely congenital in nature or largely genetically determined. These include disorders that may cause ischemic stroke, hemorrhagic stroke, and structural cerebrovascular entities.

SUBARACHNOID HEMORRHAGE/INTRACRANIAL ANEURYSM

The evaluation and management of subarachnoid hemorrhage (SAH) and intracranial saccular aneurysm were addressed in Chapters 14 and 17. Population-based studies have suggested that there is an increased occurrence of a first- or second-degree relative having had an SAH, with 20% noted in one study. In first-degree relatives, nearly 10% have a history of SAH, or intracranial aneurysm, far higher than would be expected in the general population.

From a screening perspective, among first-degree relatives of patients who had intracranial aneurysm and were 30 years or older and in families in which at least two members of the family had an intracranial aneurysm, 9% had an aneurysm confirmed. Cigarette smoking, female gender, and hypertension are risk factors for the occurrence of intracranial aneurysm in those with a family history. Magnetic resonance angiography (MRA) screening in first-degree relatives of those who had ruptured intracranial aneurysm and no known family history of intracranial aneurysm indicated that only 3% of first-degree relatives who were between the ages of 20 and 70 years and screened with MRA had an aneurysm detected. The highest risk was noted in siblings as opposed to their children. Risk factors for a slightly higher risk for aneurysm detection included female gender, older age, family history of polycystic kidney disease, history of hyperlipidemia, history of hypertension, and presence of hyperglycemia. In general, screening with MRA or computed tomography angiography is recommended for at least first-degree relatives if two or more members of their family have a history of brain aneurysm or SAH (particularly if the affected are first-degree relatives). Initial screening is typically performed between the ages of 20 and 30 years, unless there are members of the family who had an intracranial aneurysm detected at a younger age. If the initial screening is negative, then intermittent repeat imaging is indicated given that an initial negative screening study does not preclude subsequent formation of an aneurysm.

Among familial cases, the mean age of SAH patients is younger, and in later generations, SAH occurs at a younger age. The overall outcome may also be poorer in familial cases. Heritable disorders that are associated with intracranial aneurysm include autosomal dominant polycystic kidney disease, neurofibromatosis type 1, pseudoxanthoma elasticum, tuberous sclerosis, Marfan syndrome,
Ehlers-Danlos syndrome type IV, Klinefelter syndrome, microcephalic osteodysplastic primordial dwarfism, and hereditary hemorrhagic telangiectasia (HHT).

CEREBRAL INFARCTION

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke disease that is caused by a mutation of the NOTCH3 receptor gene on chromosome 19. The disorder typically begins in early or middle adulthood, with patients presenting with migraine, cerebral infarction, psychiatric disorders, or cognitive impairment. Recurrent subcortical cerebral infarctions may lead to a stepwise decline and dementia and result in reduced survival. The arteriopathy develops slowly, resulting in destruction of smooth muscle cells and thickening and fibrosis of the walls of small- and medium-sized penetrating arteries with consequent narrowing of the lumen. This impairs cerebral blood flow and produces characteristic white matter hyperintensities in T2-weighted magnetic resonance imaging (MRI) on the basis of which CADASIL may be diagnosed well before the first clinically apparent stroke. Multiple lacunar infarcts, mainly in the frontal white matter and basal ganglia, lead to progressive permanent brain damage manifested as cognitive decline and finally as dementia. Involvement of the anterior aspect of the temporal lobe is typical of the disorder. Microhemorrhages may be noted on MRI in about one-third of patients. Although the symptoms are almost exclusively neurologic, the arteriopathy is generalized and pathologic diagnosis is possible via skin biopsy in which osmophilic granules can be detected on electron microscopy (accumulation of pathognomonic basophilic, periodic acid-Schiff-positive, and, in electron microscopy, osmophilic material between degenerating smooth muscle cells in dermal arteries). The findings are highly specific, but the sensitivity is somewhat less than 100%. In addition to the suggestive family history and clinical features, diagnosis can be suggested on the basis of an MRI. The blood can be tested for the NOTCH3 mutation. Once the diagnosis is made, the homocysteine level should be checked because there is some suggestion that these patients may be at higher risk for hyperhomocysteinemia. There are no proven therapies that will alter the course of CADASIL or reduce the risk for recurrent cerebral infarction. Treatment for CADASIL includes use of antiplatelet agents, although the efficacy is not clear. The effectiveness of aggressive atherosclerosis risk factor control is uncertain but typically is implemented. Because MRI scanning may frequently reveal microhemorrhages in people with CADASIL, more aggressive antiplatelet agents and anticoagulation are not usually recommended. Use of medications for dementia, such as acetylcholinesterase inhibitors as used in Alzheimer’s dementia, is of unclear efficacy.

MITOCHONDRIAL DISORDERS

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is maternally inherited and caused by mitochondrial DNA mutations, with a substitution of adenine or guanine at position 3243 (A3243G) causing 80% of cases. Patients present with intermittent confusion, migraine headaches, cerebral infarction before the age of 40 years, lactic acidosis in the blood, possible focal or generalized seizures, muscle biopsy showing ragged red fibers, and
encephalopathy. Imaging may demonstrate ischemic stroke-like lesions, particularly affecting the occipital lobes and basal ganglia. No specific treatments are clearly efficacious. Patients sometimes are treated with coenzyme Q10, vitamin C, carnitine, and riboflavin, but the effect of any of these is uncertain. Valproic acid should not be given to patients with MELAS or other known inborn errors of mitochondrial metabolism as it may trigger or aggravate seizures or other neurologic impairment in such individuals.

FABRY DISEASE

Fabry disease is an X-linked disorder that is caused by a mutation in the alpha-galactosidase A gene. Neurologic presentations include burning pain in a “glove and stocking” distribution caused by small-fiber peripheral neuropathy, and others may present with cerebral infarctions, most commonly affecting small arteries but also sometimes affecting the larger arteries. Some of the strokes may be caused by hypertension-induced small artery occlusive disease. The ischemic strokes are caused mainly by thrombosis in the setting of small artery occlusive disease. The findings of skin angiokeratomas (typically found between the umbilicus and the knees), progressive renal disease, and a specific type of corneal dystrophy known as whorl keratopathy also suggest the diagnosis. The disorder is caused by deficient lysosomal galactosidase A activity. Deposits of globotriaosylceramide 3 then accumulate in the endothelium and smooth muscle, including the arteries, the cornea, and throughout the nervous system.

Diagnosis can be made by a skin biopsy showing the membrane-bound electron-dense bodies in the fibroblasts and endothelial cells and also by evaluating the level of alpha-galactosidase activity in the plasma or peripheral leukocytes. The diagnosis is more difficult in women because these levels may be normal. Enzyme replacement therapy is typically used although the efficacy in cerebral ischemia prevention is not known. Likewise, the effectiveness of any other medical therapy such as antiplatelet therapy is not certain. Cardiac abnormalities may also lead to brain embolism.

HOMOCYSTINURIA

Homocystinuria is an autosomal recessive disorder of amino acid metabolism that most typically is caused by a defect in the gene that leads to the production of the enzyme cystathionine beta-synthase. It may also be caused by deficiencies in the production of 5,10-methylene tetrahydrofolate reductase or homocysteine methyltransferase. The autosomal recessive disease leads to elevation of homocysteine and its metabolites in the plasma and urine. The endothelial accumulation of homocysteine leads to premature atherosclerosis and also increased platelet adhesion. Both arterial and venous thrombosis may occur. In addition to thrombosis and premature atherosclerosis, clinical features include eye abnormalities such as optic atrophy, ectopic lens, or glaucoma; marfanoid appearance; high arched palate; mental retardation; seizures; osteoporosis; and scoliosis. Patients are treated with high-dose pyridoxine, folic acid, and vitamin B₁₂. A diet that is low in methionine and high in cystine should also be considered.

SICKLE CELL DISEASE

Sickle cell disease is an autosomal recessive disorder that occurs in 1 in 500 births in African Americans. Although much less common, it can affect people of other
ethnicities. The disorder commonly leads to cerebral infarction, which occurred in 8% of children by the age of 14 years in a large cohort study. In another, the occurrence of the first stroke was 11% at the age of 20 years and 24% at the age of 45 years. Red cells that contain hemoglobin SS and are exposed to low oxygen tension alter their structure, leading to increased blood viscosity and the potential for multiple small artery occlusions. Larger arteries can also become affected through adverse changes in the small arteries that supply the arterial wall. The strokes can be either ischemic or hemorrhagic, with ischemic strokes being most common in children and intracerebral hemorrhages (ICHs) and SAHs occurring preferentially in adults. The carotid system is most commonly affected in children. Other cerebrovascular manifestations may include cortical vein and venous sinus thromboses. From a pathologic standpoint, the arterial damage leads to intimal hyperplasia with clot formation leading to ischemia. Occasionally, bilateral internal carotid arterial stenoses may cause an arteriographic appearance that mimics Moyamoya disease.

The sickle cell crisis may be precipitated by hypoxia, physical exertion, stress, or acute infection. Transcranial Doppler (TCD) studies may be used to define children who are at highest risk for experiencing a cerebral infarction. Those with TCD velocities less than 200 cm per second are at the highest stroke risk. In the Stroke Prevention in Sickle Cell Disease (STOP) trial, children were randomly assigned to either intermittent transfusions or standard care. The goal was to keep the hemoglobin S level more than 30% and the transfusion therapy was highly effective in reducing the risk for first stroke. In adults, chronic intermittent transfusions are often considered, but a complete evaluation is necessary to determine whether there is any other cause of the infarction. In addition to transfusion, aggressive hydration, oxygenation, and pain control are implemented.

ICH

Amyloid Angiopathy

Cerebral amyloid angiopathy and its potential for causing intracranial hemorrhage are reviewed in Chapter 17. Amyloid angiopathy can be familial, in heredity cerebral hemorrhage with amyloidosis of the Dutch type. This autosomal dominant disorder leads to amyloid deposition in the small intracranial arteries. Patients present with recurrent lobar ICHs or with vascular dementia. There is another autosomal dominant disorder, hereditary cerebral hemorrhage with amyloidosis of the Icelandic type, which is caused by a different gene mutation but with similar clinical findings.

Cerebral Malformations

Cavernous Malformations

Intracranial cavernous malformations are commonly noted on MRI and typically are angiographically occult legions. They may occur in families, with inheritance in an autosomal dominant manner. A single gene mutation may occur in one or more of three genes, CCM1 (chromosome 7), CCM2 (chromosome 7), and CCM3 (chromosome 3). Familial cavernous malformations may particularly occur in those of Hispanic background, caused by a mutation in CCM1. Overall, no specific gene mutation may be detected in about 1 in 10 with a family history of cavernous malformation. People with familial CMs will typically have multiple lesions. The natural history of intracranial cavernous malformations is described in Chapter 30.

HHT

HHT, also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that involves abnormalities of chromosome 9 or 12. Arteriovenous malformations (AVMs) commonly occur in these families intracranially and in the lung, liver, and kidney. ICH and cerebral infarction that is caused by paradoxic embolus through the pulmonary AVM can both occur. Other manifestations of brain AVMs may include seizures and focal neurologic deficits. The management of an AVM is summarized in Chapters 17 and 30. AVMs may be treated with surgical excision, endovascular therapy, or radiosurgery. Epistaxis, gastrointestinal bleeding, shortness of breath or hemoptysis caused by the pulmonary AVMs, and skin and mucus membrane telangiectasias all may be noted. In one study of 321 patients who had HHT and were observed at a single institution, 3.7% had a history of cerebral malformations, with 2.1% presenting with intracranial hemorrhage. In addition to AVMs, cavernous malformations and venous malformations may be seen. It is suggested that the risk for having a hemorrhage from AVMs in the setting of HHT is lower than from nonfamilial AVMs. A history of cerebral infarction or transient ischemic attack is more common than hemorrhagic disease.