Dyschromatosis Symmetrica Hereditaria
In a patient with dyschromatosis symmetrica hereditaria (DSH; 127400) associated with dystonia, mental deterioration, and tissue calcification, Tojo et al. (2006) detected a heterozygous G-to-A transition at nucleotide 3019 in exon 11 of the ADAR gene, resulting in a gly-to-arg substitution at codon 1007 (G1007R). The patient was observed at age 3 to have pea-sized pigmented macules on her face. The small hyper- and hypopigmented macules spread gradually to the dorsal aspect of her extremities. School record and motor function were normal. She developed neurologic symptoms including gait disturbance and dystonic posturing of the legs at 17 years of age and became wheelchair-bound by age 22. Intellectual deterioration started at age 21 years of age. CT showed calcification of basal ganglia, cerebral white matter, and dentate nucleus of cerebellum. The father had had typical skin lesions of DSH, noted at age 2 years, and lost the ability to ride a motorbike in adult life with the development of intellectual deterioration. No brain imaging was reported, and he died of calcific aortic valve stenosis at age 38 years. The mother was negative for the mutation.
Kondo et al. (2008) described an 11-year-old male DSH patient with dystonia, mental deterioration, and brain calcification. He developed neurologic features at age 3, including loss of intellectual skills and axial torsion dystonia. CT scan showed basal ganglia, cerebral white matter, and dentate nucleus calcification. The origin of mutation was maternal. The mother had faint hypopigmented macules on the dorsa of the fingers but no neurologic features reported, nor was her age stated.
Aicardi-Goutieres Syndrome
In 2 individuals, 1 of Brazilian origin and 1 of European American origin, with Aicardi-Goutieres syndrome-6 (AGS6; 615010), Rice et al. (2012) identified a heterozygous de novo mutation in exon 11 of the ADAR gene: a G-to-A transition at nucleotide 3019, resulting in a gly-to-arg substitution at codon 1007 (G1007R). Using an ADAR1 editing substrate, miR376-a2 (610960), Rice et al. (2012) found that, of 6 ADAR mutations tested, only the G1007R variant showed a significant effect on editing, with levels of editing equivalent to those seen with inactive protein. The proximity of G1007R to the RNA backbone and the possibility for an arginine residue to make polymorphic interactions there suggested a mechanism whereby arg1007 might confer a dominant-negative effect: by binding more tightly to RNA the mutant protein could act as a competitive inhibitor of wildtype protein while being itself catalytically inactive. Rice et al. (2012) found that a plasmid expressing G1007R ADAR1 showed stronger inhibition of wildtype ADAR1 than equivalent amounts of a plasmid expressing catalytically inactive ADAR1.
In 2 half-sibs with AGS6, Livingston et al. (2014) found the G1007R mutation in heterozygosity.
In a 5-year-old boy, born of unrelated Hispanic parents, with onset of nonsyndromic spastic paraplegia at age 2 years following normal psychomotor development, Crow et al. (2014) identified a de novo heterozygous G1007R mutation in the ADAR1 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Brain imaging and cognition were normal, and laboratory studies showed increased interferon. Crow et al. (2014) emphasized the emerging phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder.