Aicardi-Goutieres Syndrome 6

A number sign (#) is used with this entry because of evidence that Aicardi-Goutieres syndrome-6 (AGS6) is caused by homozygous or compound heterozygous mutation in the ADAR gene (146920) on chromosome 1q21.

Dyschromatosis symmetrica hereditaria (127400) is an allelic disorder.

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

Rice et al. (2012) reported 10 families with 14 children, including 1 set of identical twins, with Aicardi-Goutieres syndrome. The families were of diverse ethnic backgrounds including Norwegian, Italian, Pakistani, Brazilian, Indian, British, Spanish, mixed Italian/Cuban, and European American. Two of the families were consanguineous. Clinical details included intracranial calcification and severe developmental delay in all, leukodystrophy in most, and markedly elevated cerebrospinal fluid (CSF) interferon-alpha (see 147660) in all in whom it was measured.

Clinical Variability

Livingston et al. (2014) reported 9 patients, including 2 sibs and 2 half-sibs, with refractory dystonia starting between ages 9 months and 5 years. Eight of the patients showed normal psychomotor development before symptom onset; the ninth patient had mild-to-moderate global developmental delay apparent in early infancy. Six of the 9 children presented between 9 and 18 months with acute onset of severe generalized dystonia in the context of a nonspecific febrile illness, such as ear infection, respiratory illness, or viral illness with rash. Clinical features included limb tremor and stiffening, rigidity, loss of previous motor and other developmental skills, and severe dystonia affecting all 4 limbs. These neurologic abnormalities developed and progressed rapidly within several weeks, and were refractory to pharmacologic management. Two additional patients had a slower course, with progressive dystonia and neurologic deterioration over several months. Three patients were retrospectively noted to have cutaneous pigmentation with freckling of the face and hands; only 1 child had vasculitic skin lesions. Brain MRI from 7 patients showed bilateral striatal necrosis, with signal changes in the caudate and putamen, often associated with swelling and later shrinkage. Three patients had evidence of intracranial calcifications, and 1 had findings suggestive of calcification. All 7 patients analyzed had blood evidence of upregulation of interferon-stimulated genes, the so-called interferon signature, even years after symptom onset. Livingston et al. (2014) suggested that the interferon signature may be a reliable screening test for this disorder.

Crow et al. (2014) reported a 5-year-old boy, born of unrelated Hispanic parents, who presented at age 2 years with toe walking and frequent falls associated with slowly progressive spastic paraplegia following normal early psychomotor development. Physical examination showed lower limb spasticity with increased tone, ankle clonus, unilateral extensor plantar response, and spastic diplegic gait. Brain imaging and cognition were normal. Exome sequencing identified a de novo heterozygous mutation in the ADAR1 gene (G1007R; 146920.0011) that had been identified in patients with classic AGS6. Laboratory studies revealed evidence of 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 transmission pattern of AGS6 in the families reported by Rice et al. (2012) was consistent with autosomal recessive inheritance.

By whole-exome sequencing in 4 probands with a diagnosis of Aicardi-Goutieres syndrome in whom mutations in known causative genes had been excluded, Rice et al. (2012) identified compound heterozygous or homozygous mutations in the ADAR1 gene. They sequenced other individuals without known mutations from their AGS cohort and identified a total of 9 distinct mutations, including 1 recurrent missense mutation, pro193 to ala (P193A; 146920.0007). Two unrelated affected individuals harbored a heterozygous de novo missense mutation, gly1007 to arg (G1007R; 146920.0011). This mutation appeared to have a dominant-negative effect. Of the 8 amino acid substitutions identified, 7 involved residues situated in the catalytic domain of ADAR1; 5 of these 7 (arg892, lys999, gly1007, tyr1112, and asp1113) lie along the surface of the protein that interacts with double-stranded RNA, and the 2 others (ala870 and ile872) lie internal to the domain structure and are predicted to destabilize the protein. In contrast, pro193 is positioned within the Z-DNA/Z-RNA-binding domain. In the wildtype protein, pro193 makes direct contact with the nucleic acid, and substitution of this residue with alanine removes important atomic interactions between the protein and DNA/RNA.

Rice et al. (2012) noted that the G1007R mutation in ADAR1 had previously been reported (see 146920.0011) in 2 individuals with dyschromatosis symmetrica hereditaria (DSH; 127400) who also demonstrated neurodegeneration with dystonia and intracranial calcification. The skin lesions typical of DSH had not been reported in AGS (they are distinct from AGS-related chilblains) and no individual with AGS6 had obvious features of DSH. Of note, DSH has only rarely been reported outside of Japan and China. Moreover, marked variability in expression of DSH is well recognized even within families. Rice et al. (2012) remarked that although their findings did not necessarily implicate dysregulation of type 1 interferon in the DSH phenotype, they suggested that missense and null heterozygous mutations in ADAR1 are consistent with both DSH and with carrier or affected status for AGS. Thus, Rice et al. (2012) suggested that the lack of DSH skin features in their AGS cases and their heterozygous parents most likely relates to nonpenetrance and/or variable expressivity due to ancestry or other genetic or nongenetic factors.

In 7 patients, including 2 sibs, with atypical AGS6 presenting as bilateral striatal necrosis with severe dystonia, Livingston et al. (2014) identified compound heterozygous mutations in the ADAR gene (see, e.g., 146920.0007; 146920.0016). Six of the patients carried the P193A mutation on 1 allele. Two additional half-sibs with the disorder were found to carry a heterozygous G1007R missense mutation; the second mutation was likely not detected in these patients. Functional studies of the variants were not performed. No interferon signature was found in 4 children with a similar disorder who did not have ADAR mutations.