A number sign (#) is used with this entry because of evidence that Aicardi-Goutieres syndrome-7 (AGS7) is caused by heterozygous gain-of-function mutation in the IFIH1 gene (606951) on chromosome 2q24.

Aicardi-Goutieres syndrome-7 (AGS7) is an autosomal dominant inflammatory disorder characterized by severe neurologic impairment. Most patients present in infancy with delayed psychomotor development, axial hypotonia, spasticity, and brain imaging changes, including basal ganglia calcification, cerebral atrophy, and deep white matter abnormalities. Laboratory evaluation shows increased alpha-interferon (IFNA1; 147660) activity with upregulation of interferon signaling and interferon-stimulated gene expression. Some patients may have normal early development followed by episodic neurologic regression (summary by Rice et al., 2014).

For a phenotypic description and a discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).

Rice et al. (2014) reported 8 children with a neurodevelopmental disorder associated with inflammatory markers. Five patients presented with classic clinical features of AGS, including neonatal or infantile onset of growth retardation, irritability, poor feeding, axial hypotonia, and delayed psychomotor development. The most severely affected patients had microcephaly, spastic-dystonic tetraparesis, and lack of speech. Brain imaging showed cerebral atrophy with basal ganglia calcifications and abnormal T2-weighted signal abnormalities in the deep white matter. One patient had a lupus (SLE; 152700)-like disease with vasculitic rash, lymphadenopathy, serositis with pericardial effusion, and abnormal serum autoantibodies, whereas another had acute nephrotic syndrome. Two of the severely affected patients died in early childhood. Two unrelated patients showed normal psychomotor development until about 13 to 15 months, after which they had acute onset of neurologic regression with loss of motor and intellectual skills and onset of spasticity and dystonia. One patient had a unique phenotype characterized by onset of lower-limb spasticity and acute neurologic deterioration around age 3 years. These changes were associated with brain imaging abnormalities, including cerebral atrophy and deep white matter changes. She developed a multisystem inflammatory disorder with autoantibodies, hair loss, and a livedo rash. Her 33-year-old father had slowly progressive childhood-onset lower-limb spasticity and borderline-positive antinuclear autoantibodies. All patients had laboratory evidence of increased alpha-interferon activity with upregulation of interferon signaling and interferon-stimulated gene expression.

Oda et al. (2014) reported 3 unrelated Japanese patients with AGS7. Two patients presented around 6 months of age with developmental delay, and the third presented at 4 days of age with omphalitis and thrombocytopenia. Features common to all patients included progressive microcephaly, severe developmental delay beginning in early infancy, and spastic quadriplegia. Two patients had seizures and 2 had dystonia. Laboratory studies showed serum autoantibodies and a type 1 interferon signature. Two patients had hypergammaglobulinemia, hypocomplementemia, thrombocytopenia, and increased serum transaminases. Brain imaging in all children showed basal ganglia calcifications, brain atrophy, and white matter abnormalities. None of the patients developed chilblain lesions.

Buers et al. (2017) reported a 6-year-old boy with recurrent febrile episodes, bilateral spasticity, developmental delay, and basal ganglia calcification, and mutation in the IFIH1 gene. Right facial droop was noted at 4 weeks of age. Over the next 6 months he experienced persistent oral mucositis and recurrent ear infections, and later recurrent upper respiratory tract infections. At age 6 months, he developed a pruritic well-defined erythematous lesion on his right flank, which slowly progressed in size; biopsy revealed findings consistent with inflammatory linear verrucous epidermal nevus. Bilateral nephrocalcinosis was noted on abdominal ultrasound. He had failure to thrive with weight loss at 9 months of age, requiring significant caloric supplementation. He had developmental delay, being able to pull and stand at 12 months, but those gross motor milestones were lost at age 15 months, at which time he experienced general muscular hypotonia, worsening of the facial palsy, and a flare of the right flank rash. In the second and third years of life he had recurrent joint pain and stiffness, and over the next several years developed a spastic gait and contractures of the knee joints and elbows. Brain CT scan at age 6 years showed bilateral calcification of the basal ganglia.

Adang et al. (2018) described 3 patients with AGS7 who had typical features of the syndrome but also presented with pulmonary hypertension, 1 at age 16 years, 1 at 7 years, and 1 at 1 month of age. Two of these patients had died. All had gastrointestinal manifestations including hepatitis, poor weight gain, and feeding intolerance, and dermatologic manifestations including vasculitic rashes, psoriasis, and eczema. Two of the 3 had CNS perivascular calcifications.

Amari et al. (2020) reported a female infant who was found on prenatal ultrasound at 16 weeks' gestation to have a single umbilical artery, intestinal hyperechogenicity, and mitral valve regurgitation. The mitral valve regurgitation resolved spontaneously. However, she was delivered at 29 weeks and 4 days of gestation when prenatal ultrasound showed cardiomegaly, pericardial effusion, splenomegaly, and intracranial calcification. At birth, she was found to have hepatosplenomegaly and 'blueberry muffin' spots on her skin. Laboratory studies showed elevated direct bilirubin and aspartate transaminase levels, anemia, thrombocytopenia, and coagulopathy. Lenticulostriate vasculopathy was seen on head ultrasound. Bilateral cystic periventricular leukomalacia was diagnosed at 20 days of life. She developed pulmonary hypertension, respiratory distress, right-sided heart failure, and ascites. She died at 3 months of age from respiratory failure and pulmonary hypertension.

Clinical Variability

Crow et al. (2014) reported a man, born of unrelated British Caucasian parents, who presented at age 2 years with toe walking associated with slowly progressive spastic paraplegia following normal early psychomotor development. At age 33 years, he showed lower limb spasticity without upper limb involvement. Brain imaging and cognition were normal at the age of 29 years. Exome sequencing identified a de novo heterozygous mutation in the IFIH1 gene (G495R; 606951.0005) that had been identified in another family with a relatively mild form of AGS7. Laboratory studies revealed persistently increased interferon. Crow et al. (2014) emphasized the phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder.

The heterozygous mutations identified in 5 of the 8 families with AGS7 reported by Rice et al. (2014) occurred de novo; in 2 families, the transmission pattern was consistent with autosomal dominant inheritance and incomplete penetrance, and in 1 family, the parental DNA was not available.

In 8 probands with AGS7, Rice et al. (2014) identified 6 different heterozygous mutations in the IFIH1 gene (606951.0001-606951.0006). The first 3 mutations were found by whole-exome sequencing. The mutations in 5 of the probands occurred de novo, whereas in 2 they were transmitted; parental DNA was not available for 1 proband. In 1 family, 2 mutation carriers remained clinically unaffected as adults. In vitro functional expression assays in HEK293T cells showed that the mutations caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA), whereas control cells did not. The mutations also conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. The mutated residues were located on the surface of the RNA-binding and ATP-binding sites in conserved helicase domains, but ATP hydrolysis activity of the mutants was comparable to wildtype. Structural modeling and biochemical studies indicated that the mutations enhance the stability of the activated IFIH1 filament by increasing affinity for dsRNA. These findings were consistent with a gain of function, resulting in increased interferon signaling. The findings also suggested the presence of an undefined endogenous dsRNA capable of stimulating mutant receptors.

In 3 unrelated Japanese patients with AGS7, Oda et al. (2014) identified 3 different de novo heterozygous missense mutations in the IFIH1 gene (606951.0002; 606951.0007; and 606951.0008). The mutations were found by trio-based whole-exome sequencing. Peripheral blood cells from the patients showed a type 1 interferon signature, and expression of each of the mutations in a human hepatoma cell line resulted in increased activation of the IFNB1 (147640) promoter compared to wildtype, consistent with increased type I interferon production.

In a 6-year-old boy with recurrent febrile episodes, bilateral spasticity, developmental delay, and basal ganglia calcification, Buers et al. (2017) identified heterozygosity for the recurrent R822Q mutation (606951.0009) in the IFIH1 gene, previously reported in patients with Singleton-Merten syndrome (SGMRT1; 182250). The mutation was not present in parental DNA and was considered to have arisen de novo. The proband's interferon signature pattern showed upregulation of IFN-induced gene expression.

Adang et al. (2018) reported 3 new AGS7 patients with typical features of the disorder and pulmonary hypertension. These 3 patients had missense mutations in the IFIH1 gene that were shown to be de novo in 2 cases. One patient had the previously reported arg337-to-gly (R337G) mutation (606951.0003).

In a female infant with AGS7, Amari et al. (2020) identified a de novo heterozygous mutation in the IFIH1 gene (E813D; 606951.0010). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing.