Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.
Am. J. Med. Genet.. 2015-01-16; 167(2): 296-312
DOI: 10.1002/ajmg.a.36887
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1. Am J Med Genet A. 2015 Feb;167A(2):296-312. doi: 10.1002/ajmg.a.36887. Epub 2015
Jan 16.
Characterization of human disease phenotypes associated with mutations in TREX1,
RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.
Crow YJ(1), Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL,
Oojageer A, Anderson B, Pizzino A, Helman G, Abdel-Hamid MS, Abdel-Salam GM,
Ackroyd S, Aeby A, Agosta G, Albin C, Allon-Shalev S, Arellano M, Ariaudo G,
Aswani V, Babul-Hirji R, Baildam EM, Bahi-Buisson N, Bailey KM, Barnerias C,
Barth M, Battini R, Beresford MW, Bernard G, Bianchi M, Billette de Villemeur T,
Blair EM, Bloom M, Burlina AB, Carpanelli ML, Carvalho DR, Castro-Gago M,
Cavallini A, Cereda C, Chandler KE, Chitayat DA, Collins AE, Sierra Corcoles C,
Cordeiro NJ, Crichiutti G, Dabydeen L, Dale RC, D’Arrigo S, De Goede CG, De Laet
C, De Waele LM, Denzler I, Desguerre I, Devriendt K, Di Rocco M, Fahey MC, Fazzi
E, Ferrie CD, Figueiredo A, Gener B, Goizet C, Gowrinathan NR, Gowrishankar K,
Hanrahan D, Isidor B, Kara B, Khan N, King MD, Kirk EP, Kumar R, Lagae L,
Landrieu P, Lauffer H, Laugel V, La Piana R, Lim MJ, Lin JP, Linnankivi T, Mackay
MT, Marom DR, Marques Lourenço C, McKee SA, Moroni I, Morton JE, Moutard ML,
Murray K, Nabbout R, Nampoothiri S, Nunez-Enamorado N, Oades PJ, Olivieri I,
Ostergaard JR, Pérez-Dueñas B, Prendiville JS, Ramesh V, Rasmussen M, Régal L,
Ricci F, Rio M, Rodriguez D, Roubertie A, Salvatici E, Segers KA, Sinha GP, Soler
D, Spiegel R, Stödberg TI, Straussberg R, Swoboda KJ, Suri M, Tacke U, Tan TY, te
Water Naude J, Wee Teik K, Thomas MM, Till M, Tonduti D, Valente EM, Van Coster
RN, van der Knaap MS, Vassallo G, Vijzelaar R, Vogt J, Wallace GB, Wassmer E,
Webb HJ, Whitehouse WP, Whitney RN, Zaki MS, Zuberi SM, Livingston JH, Rozenberg
F, Lebon P, Vanderver A, Orcesi S, Rice GI.
Author information:
(1)INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris
Descartes – Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker,
Paris, France; Manchester Centre for Genomic Medicine, Institute of Human
Development, Faculty of Medical and Human Sciences, Manchester Academic Health
Sciences Centre, University of Manchester, Manchester, UK.
Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations
in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report
on 374 patients from 299 families with mutations in these seven genes. Most
patients conformed to one of two fairly stereotyped clinical profiles; either
exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where
data were available), or a post-natal presentation, usually within the first year
of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a
loss of previously acquired skills. Other clinically distinct phenotypes were
also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and
non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths
(19.3% of patients with follow-up data). Of 285 patients for whom data were
available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and
intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy,
intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic
lupus erythematosus were seen frequently enough to be confirmed as real
associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust
relationship between mutations in all seven genes with increased type I
interferon activity in cerebrospinal fluid and serum, and the increased
expression of interferon-stimulated gene transcripts in peripheral blood. We
recorded a positive correlation between the level of cerebrospinal fluid
interferon activity assayed within one year of disease presentation and the
degree of subsequent disability. Interferon-stimulated gene transcripts remained
high in most patients, indicating an ongoing disease process. On the basis of
substantial morbidity and mortality, our data highlight the urgent need to define
coherent treatment strategies for the phenotypes associated with mutations in the
Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a
window of therapeutic opportunity exists relevant to the majority of affected
patients and indicate that the assessment of type I interferon activity might
serve as a useful biomarker in future clinical trials.
© 2015 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.36887
PMCID: PMC4382202
PMID: 25604658 [Indexed for MEDLINE]