Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome.
OBJECTIVE
Aicardi-Goutières syndrome (AGS) is an early-onset encephalopathy resembling congenital viral infection that is characterized by basal ganglia calcifications, loss of white matter, cerebrospinal fluid (CSF) lymphocytosis, and elevated interferon-alpha levels in the CSF. Studies have shown that AGS is an autosomal-recessive disease linked to mutations in 5 genes, encoding the 3'-repair DNA exonuclease 1 (TREX1), the 3 subunits of ribonuclease H2 (RNASEH2A-C), and sterile alpha motif domain and HD domain-containing protein 1 (SAMHD1). In this study we further characterized the phenotypic spectrum of this disease.


METHODS
Clinical and laboratory data were obtained from 26 patients fulfilling the clinical diagnostic criteria for AGS. Genomic DNA was screened for mutations in all 5 AGS genes by direct sequencing, and sera were analyzed for autoantibodies.


RESULTS
In 20 patients with AGS, 20 mutations, 12 of which were novel, were identified in all 5 AGS genes. Clinical and laboratory investigations revealed a high prevalence of features (some not previously described in patients with AGS) that are commonly seen in patients with systemic lupus erythematosus (SLE), such as thrombocytopenia, leukocytopenia, antinuclear antibodies, erythematous lesions, oral ulcers, and arthritis, which were observed in 12 (60%) of 20 patients with AGS. Moreover, the coexistence of AGS and SLE, was for the first time, demonstrated in 2 patients with molecularly proven AGS.


CONCLUSIONS
These findings expand the phenotypic spectrum of lupus erythematosus in AGS and provide further insight into its disease mechanisms by showing that activation of the innate immune system as a result of inherited defects in nucleic acid metabolism could lead to systemic autoimmunity.
Ramantani
Georgia
G
Technische Universität Dresden, Dresden, Germany.
Kohlhase
Jürgen
J
Hertzberg
Christoph
C
Innes
A Micheil
AM
Engel
Kerstin
K
Hunger
Susan
S
Borozdin
Wiktor
W
Mah
Jean K
JK
Ungerath
Kristina
K
Walkenhorst
Hartmut
H
Richardt
Hans-Helmut
HH
Buckard
Johannes
J
Bevot
Andrea
A
Siegel
Corinna
C
von Stülpnagel
Celina
C
Ikonomidou
Chrysanthy
C
Thomas
Kara
K
Proud
Virginia
V
Niemann
Frank
F
Wieczorek
Dagmar
D
Häusler
Martin
M
Niggemann
Pascal
P
Baltaci
Volkan
V
Conrad
Karsten
K
Lebon
Pierre
P
Lee-Kirsch
Min Ae
MA
D000293:Adolescent; D000328:Adult; D020274:Autoimmune Diseases of the Nervous System / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D001927:Brain Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004421:Dystonia / Q000453:epidemiology / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D007223:Infant; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009123:Muscle Hypotonia / Q000453:epidemiology / Q000235:genetics; D020125:Mutation, Missense; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D016914:Ribonuclease H / Q000235:genetics*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D055815:Young Adult
D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; C091139:ribonuclease HII; D016914:Ribonuclease H; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins