Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.
OBJECTIVE
To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1.


METHODS
We used clinical and radiological description and molecular analysis.


RESULTS
Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin.


CONCLUSIONS
Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1.
Ramesh
Venkateswaran
V
Department of Paediatric Neurology, Newcastle General Hospital, Newcastle upon Tyne, UK.
Bernardi
Bruno
B
Stafa
Altin
A
Garone
Caterina
C
Franzoni
Emilio
E
Abinun
Mario
M
Mitchell
Patrick
P
Mitra
Dipayan
D
Friswell
Mark
M
Nelson
John
J
Shalev
Stavit A
SA
Rice
Gillian I
GI
Gornall
Hannah
H
Szynkiewicz
Marcin
M
Aymard
François
F
Ganesan
Vijeya
V
Prendiville
Julie
J
Livingston
John H
JH
Crow
Yanick J
YJ
D016893:Carotid Stenosis / Q000235:genetics / Q000503:physiopathology; D002539:Cerebral Arterial Diseases / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005090:Exodeoxyribonucleases; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007223:Infant; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D010750:Phosphoproteins; D017354:Point Mutation / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D000076106:SAM Domain and HD Domain-Containing Protein 1
D010750:Phosphoproteins; D011506:Proteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins