pnas201104699 232..232


LETTER

Cerebral vasculopathy is a common
feature in Aicardi–Goutières
syndrome associated with
SAMHD1 mutations

In their recent interesting paper, Xin et al. (1) described an
autosomal recessive condition in 14 individuals of Old Order
Amish ancestry characterized by cerebral vasculopathy and early
onset stroke. The affected patients presented a heterogeneous
phenotype, including variable developmental disability, irrita-
bility in infancy, chilblain lesions, glaucoma, and arthritis.
Through genome-wide homozygosity mapping and candidate
gene sequencing, the authors identified the homozygous muta-
tion c.1411-2A > G in SAMHD1 being associated with this entity.
Additionally, they detected this mutation in 3 of 44 patients
with developmental delay (phenotypes not further described).
Although mutations in SAMHD1 have been found to be disease-
causing in Aicardi–Goutières syndrome (AGS) (2), Xin et al.
(1) stated that “the phenotype reported here is apparently in-
compatible with Aicardi–Goutières syndrome” and that “none
of our 17 patients has been diagnosed with Aicardi–
Goutières syndrome.”
Although, as Xin et al. (1) explained, AGS is most commonly

recognized as “a type of encephalopathy whose clinical features
mimic those of acquired in utero viral infection,” there now
exists an extensive literature highlighting the diverse spectrum
of phenotypes that can occur in the context of AGS (an overview
is provided in ref. 3). Thus, for example, neurological dysfunc-
tion in AGS is not always progressive or, indeed, necessarily
present at all; microcephaly is not always seen; onset is not al-
ways in the first year of life; intracranial calcification and white
matter changes are not inevitable; and a cerebrospinal fluid
(CSF) lymphocytosis is absent in a considerable number of af-
fected individuals. We accept that such diversity makes clinical
diagnosis challenging. However, we consider that the clinical
findings presented by Xin et al. (1), most particularly the chil-
blain lesions, early irritability, and glaucoma, should prompt
consideration of the diagnosis. We suggest that it might be
sensible for Xin et al. (1) to confirm that intracerebral calcifi-
cations were not evident on computed tomography and that
reliable CSF indices (elevated white cells and increased titers
of IFN-α and pterins) of AGS were not present in any of their

cases (with recognition of the age-dependent nature of the
CSF findings).
Irrespective of diagnostic classification, there are two earlier

independent descriptions of cerebral arterial stenoses, stroke,
and cerebral vasculopathy in patients with AGS carrying muta-
tions in SAMHD1 (4, 5). These two papers fully encompass
the phenotypes described in the article by Xin et al. (1). In our
view, recognizing that the Old Order Amish disorder is part
of the AGS-related phenotype means that future understand-
ing of AGS disease pathogenesis will have relevance to the
Amish community also.
In summary, we would argue that Xin et al. (1) did not

present a new clinical condition but described a heterogeneous
group of Old Order Amish individuals with AGS and in-
tracerebral arteriopathy. Based on our previous work and their
findings, we conclude that intracerebral large artery disease is a
common phenomenon in patients with SAMHD1 mutations.
Interestingly, we have never observed large artery disease in
association with mutations in TREX1, RNASEH2A, RNASEH2B,
or RNASEH2C, perhaps indicating a particular role for
SAMHD1 in blood vessel integrity and homeostasis.

ACKNOWLEDGMENTS. This work was supported by a grant from the Inter-
disciplinary Center for Clinical Research Münster (to M.d.M and F.R.). Y.J.C.
acknowledges the Manchester National Institute for Health Research Bio-
medical Research Centre, the European Leukodystrophy Association, and the
European Union’s Seventh Framework Programme (FP7/2007-2013) under
Grant Agreement Number 241779.

Marcel du Moulina, Peter Nürnbergb, Yanick J. Crowc, and Frank
Rutscha,1
aDepartment of General Pediatrics, Münster University Children’s
Hospital, D-48149 Münster, Germany; bCologne Center for Ge-
nomics, University of Cologne, D-50931 Cologne, Germany; and
cGenetic Medicine, University of Manchester, Manchester Aca-
demic Heath Science Centre, Central Manchester Foundation Trust
University Hospitals, Manchester M13 9WL, United Kingdom

1. Xin B, et al. (2011) Homozygous mutation in SAMHD1 gene causes cerebral vascu-
lopathy and early onset stroke. Proc Natl Acad Sci USA 108:5372–5377.

2. Rice GI, et al. (2009) Mutations involved in Aicardi-Goutières syndrome implicate
SAMHD1 as regulator of the innate immune response. Nat Genet 41:829–832.

3. Aicardi J, Crow YJ, Stephenson JBP (2005) Aicardi–Goutières syndrome. GeneReviews.
Available at http://www.genetests.org/ [updated Nov 4, 2010].

4. Ramesh V, et al. (2010) Intracerebral large artery disease in Aicardi-Goutières syndrome
implicates SAMHD1 in vascular homeostasis. Dev Med Child Neurol 52:725–732.

5. Thiele H, et al. (2010) Cerebral arterial stenoses and stroke: Novel features of Aicardi-
Goutières syndrome caused by the Arg164X mutation in SAMHD1 are associated with
altered cytokine expression. Hum Mutat 31:E1836–E1850.

Author contributions: M.d.M., P.N., Y.J.C., and F.R. wrote the paper.

The authors declare no conflict of interest.
1To whom correspondence should be addressed. E-mail: rutschf@ukmuenster.de.

E232 | PNAS | June 28, 2011 | vol. 108 | no. 26 www.pnas.org/cgi/doi/10.1073/pnas.1104699108

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mailto:rutschf@ukmuenster.de