Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome.
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.


CONCLUSIONS
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.
Alamowitch
S
S
Tenon Hospital, Stroke Unit, Department of Neurology, Paris, France. sonia.alamowitch@tnn.aphp.fr
Plaisier
E
E
Favrole
P
P
Prost
C
C
Chen
Z
Z
Van Agtmael
T
T
Marro
B
B
Ronco
P
P
D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D000783:Aneurysm / Q000150:complications / Q000235:genetics*; D002561:Cerebrovascular Disorders / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007091:Image Processing, Computer-Assisted; D018810:Magnetic Resonance Angiography / Q000379:methods; D008279:Magnetic Resonance Imaging; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008875:Middle Aged; D009120:Muscle Cramp / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011859:Radiography; D012867:Skin / Q000473:pathology / Q000648:ultrastructure; D055815:Young Adult
D024141:Collagen Type IV