A number sign (#) is used with this entry because susceptibility to intracerebral hemorrhage (ICH) can be conferred by heterozygous mutation in the COL4A2 (120090) or COL4A1 (120130) genes, both on chromosome 13q34, or by variation in the ACE gene (106180) on chromosome 17q23.

See also ischemic stroke (601367).

Jeanne et al. (2012) reported 4 unrelated patients with adult-onset hemorrhagic stroke associated with heterozygous mutations in the COL4A2 gene (120090.0003-120090.0005). One patient was a 72-year-old white man with probable CAA (605714)-related ICH in the right occipital lobe. He had no family history of ICH, and was not taking aspirin or an anticoagulant at the time of his hemorrhage. The second was a 72-year-old white woman with a history of hypertension who developed hemorrhage in the left basal ganglia while taking aspirin. There was no family history of ICH. The third affected individual was a 45-year-old Hispanic man with a history of hypertension who developed hemorrhage in the left basal ganglia. He was not taking aspirin or anticoagulant at the time of his hemorrhage. Two sisters of this patient had ICH, although they were not available for study. The last patient was a 69-year-old African American man with probable CAA-related ICH in the right occipital lobe. He was not taking aspirin or anticoagulant at the time of his hemorrhage, and had no family history of ICH.

Weng et al. (2012) reported 2 unrelated patients with adult-onset hemorrhagic stroke associated with heterozygous mutations in the COL4A1 gene (120130.0015 and 120130.0016). One was a 73-year-old Hispanic woman who presented with a generalized tonic-clonic seizure followed by left-sided weakness in the setting of oral warfarin anticoagulation therapy for aortic valve replacement. CT showed a small right temporal ICH and MRI identified lobar microbleeds, consistent with a diagnosis of probable CAA. The second patient was a 55-year-old man of European-American ancestry who presented with a large right putamen ICH causing acute-onset left arm, face, and leg weakness, and depressed consciousness. Medical history was significant for hypertension, type 2 diabetes and low-dose aspirin use. The scenario was consistent with a diagnosis of probable hypertensive hemorrhage.

Association with the ACE Gene

Slowik et al. (2004) found an association between the ACE DD genotype (106180.0001) and spontaneous intracerebral hemorrhagic stroke in deep brain structures in 58 Polish patients (OR of 2.46). No association was found between the DD genotype and 140 controls or 70 Polish patients with small vessel disease and ischemic stroke.

Association with the COL4A2 Gene

In 4 of 96 unrelated patients with adult-onset intracerebral hemorrhage, Jeanne et al. (2012) identified 3 different pathogenic mutations in the COL4A2 gene (120090.0003-120090.0005). COL4A2 was selected as a candidate for sequencing because COL4A1 (120130), with which it forms a heterotrimer, can cause cerebrovascular disease (POREN1, 175780 and HANAC, 611773). In vitro functional expression studies showed that the COL4A2 mutations resulted in significantly decreased extracellular-to-intracellular ratios of COL4A2 and COL4A1, indicating interference with the proper secretion of both of these proteins. Intracellular immunolabeling demonstrated that the reduction in extracellular-to-intracellular COL4A1 and COL4A2 ratios resulted from retention within the endoplasmic reticulum (ER). All patients developed hemorrhagic stroke as adults, and 2 had no family history of the disorder. Jeanne et al. (2012) noted that none of the putative mutations were glycine missense variants, which, in COL4A1, are well established to underlie severe, early-onset, and highly penetrant cerebrovascular diseases. Thus, nonglycine variants may represent alleles that result in milder disease later in life or become pathogenic as a consequence of interactions with other factors that predispose to ICH.

Association with the COL4A1 Gene

In 2 of 96 patients with adult-onset hemorrhagic stroke, Weng et al. (2012) identified different heterozygous mutations in the COL4A1 gene (120130.0015 and 120130.0016). The COL4A1 gene was chosen for study because mutation in this gene can cause rare familial forms of cerebrovascular disease. In vitro cellular studies showed that both mutant proteins were retained intracellularly and impaired normal COL4A1 secretion.