Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome

Abstract

Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. The aim of this study was to describe the cerebrovascular phenotype of HANAC.

Methods: Detailed clinical data were collected in 14 affected subjects from the 3 families. MRI and magnetic resonance angiography (MRA) were performed in 9 of them. Skin biopsies were analyzed by electron microscopy in affected subjects in the 3 families.

Results: Only 2 of 14 subjects had clinical cerebrovascular symptoms: a minor ischemic stroke at age 47 years and a small posttraumatic hemorrhage under anticoagulants at age 48 years. MRI-MRA showed cerebrovascular lesions in 8 of 9 studied subjects (mean age 39.4 years, 21-57 years), asymptomatic in 6 of them. Unique or multiple intracranial aneurysms, all on the carotid siphon, were observed in 5 patients. Seven patients had a CSVD characterized by white matter changes (7/7) affecting subcortical, periventricular, or pontine regions, dilated perivascular spaces (5/7), and lacunar infarcts (4/7). Infantile hemiplegia, major stroke, and porencephaly were not observed. Skin biopsies showed alterations of basement membranes at the dermoepidermal junction associated with expansion of extracellular matrix between smooth vascular cells in the arteriolar wall.

Conclusion: The cerebrovascular phenotype in hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome associates a cerebral small vessel disease and a large vessel disease with aneurysms of the carotid siphon. It is consistent with a lower susceptibility to hemorrhagic stroke than in familial porencephaly, suggesting an important clinical heterogeneity in the phenotypic expression of disorders related to COL4A1 mutations.

Figure 1 Intracranial aneurysms in HANAC syndrome Intracranial aneurysms (arrows) or dolichoectasia (star) are shown in the 5 patients of the 3 families. Conventional angiography demonstrates multiple aneurysms on the right distal carotid artery in patient A.III.3 (A). Note an aspect of dolichoarteries of the carotid siphon. Magnetic resonance angiography (MRA) on axial slice (B) shows an aneurysm of the right distal carotid artery in patient A.IV.2. CT angiography (C) demonstrates 2 aneurysms of the right distal carotid artery with the form of glove finger in patient A.IV.4. (D) shows a right distal carotid aneurysm on axial slice of MRA in patient B.III.2. CT angiography shows multiple intracranial aneurysms of the right carotid arteries (E) and dolichoectasia (F) of the left distal carotid artery in patient C.II.3. HANAC = hereditary angiopathy with nephropathy, aneurysm, and muscle cramps.

Figure 2 White matter changes Fluid-attenuated inversion recovery (FLAIR) images show multiple periventricular and subcortical cerebral white matter changes in patients A.III.1 at age 51 years (A), A.III.3 at age 48 years (B), A.IV.2 at age 24 years (C), A.IV.4 at age 24 years (D), B.II.1 at age 57 years (E), and C.II.3 at age 57 years (F). FLAIR images denote subtentorial white matter changes of the rostral pons in patients A.III.1 (G), A.III.3 (H), and C.II.3 (I).

Figure 3 Skin basement membrane abnormalities Ultrastructural examination of skin biopsies in affected patients of the 3 families (A.IV.4 [A and D], B.II.1 [B and E], and C.II.3 [C and F]) shows segmental basement membrane (BM) replications at the dermoepidermal junction (arrow, A–C). In dermal vessels, vascular smooth muscle cells are dissociated by abnormal expansion and thickening of the BM (open arrow and asterisk, D–F).