Aicardi-Goutieres Syndrome 2

A number sign (#) is used with this entry because of evidence that Aicardi-Goutieres syndrome-2 (AGS2) is caused by homozygous or compound heterozygous mutation in the gene encoding subunit B of ribonuclease H2 (RNASEH2B; 610326) on chromosome 13q14.

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

Clinical Features

Ali et al. (2006) reported 17 children from 8 families with progressive neurodegeneration and encephalopathy beginning at birth or in infancy. Six of the families were consanguineous. All of the patients had evidence of intracranial calcification primarily affecting the basal ganglia; several had microcephaly. Laboratory studies showed lymphocytosis of the cerebrospinal fluid (CSF) and increased alpha-interferon in the CSF in most patients. Investigation for common prenatal infections was negative. The families were of multiple ethnic origins, including Algerian, Moroccan, and European.

Clinical Variability

Crow et al. (2014) reported 2 Egyptian sibs and an unrelated patient of North African descent who presented with nonsyndromic spastic paraplegia around age 2 years following normal psychomotor development. Physical examination showed scissoring gait, hypertonia, increased reflexes, ankle and patellar clonus, and extensor plantar responses. All 3 children remained ambulatory between the ages of 5 and 11 years. All had normal head size and normal cognition. Brain imaging of the 2 sibs was normal; the unrelated child had diffuse nonspecific high signal on T2-weighted imaging with some dilatation of the lateral ventricles at age 3. One of the sibs had unilateral optic atrophy, but this may have been unrelated to the primary disorder. None of the patients had increased interferon levels or chilblain skin lesions. Crow et al. (2014) emphasized the phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder.

Inheritance

The transmission pattern of AGS2 in the families reported by Ali et al. (2006) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of 10 families with Aicardi-Goutieres syndrome in whom linkage to AGS1 was excluded, Ali et al. (2006) identified a putative disease locus, termed AGS2, on chromosome 13q14-q21 (maximum multipoint lod score of 5.75 at marker D13S768). The AGS2 locus lies within a 4.7-cM region between D13S284 and D13S1309.

Molecular Genetics

In affected members of 18 unrelated families with AGS2, Crow et al. (2006) identified homozygous and compound heterozygous mutations in the RNASEH2B gene (see, e.g., 610326.0001-610326.0002). Most of the families were of European or North African descent.

In 2 Egyptian sibs and an unrelated patient of North African descent who presented with nonsyndromic spastic paraplegia around age 2 years following normal psychomotor development, Crow et al. (2014) identified a homozygous A177T mutation in the RNASEH2B gene (610326.0001). The mutation was found by exome sequencing.