ORPHA: 51, 689234; DO: 0050629;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q14.3 | Aicardi-Goutieres syndrome 2 | 610181 | Autosomal recessive | 3 | RNASEH2B | 610326 |
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.
Aicardi-Goutieres syndrome (AGS) is an autosomal recessive early-onset encephalopathy characterized by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serologic investigations for common prenatal infections (summary by Ali et al., 2006). Severe neurologic dysfunction becomes clinically apparent in infancy and manifests as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood (summary by Crow et al., 2006).
For a general phenotypic description and a discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).
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.
Tonduti et al. (2019) reported 3 patients with homozygosity for the common RNASEH2B mutation (A177T; 610326.0001) who displayed early clinical and MRI features consistent with AGS2 but showed improvement in neuroimaging including reduction in white matter hyperintensities. Patient 1 was treated with multiple courses of intravenous immunoglobulins and high-dose steroids between the ages of 21 months and 4 years, whereas the other 2 patients did not receive these interventions. Patients 1 and 3 were diagnosed with AGS2, and patient 2 was diagnosed with atypical AGS2 due to lack of cerebral calcifications, CSF lymphocytosis, elevated interferon-alpha concentrations, or a positive interferon signal. Patient 2 was intellectually normal at 4 years of age and had stable spastic diplegia. Patients 1 and 3 had global delays, but did show some developmental progression.
The transmission pattern of AGS2 in the families reported by Ali et al. (2006) was consistent with autosomal recessive inheritance.
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.
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.
Ali, M., Highet, L. J., Lacombe, D., Goizet, C., King, M. D., Tacke, U., van der Knapp, M. S., Lagae, L., Rittey, C., Brunner, H. G., van Bokhoven, H., Hamel, B., and 10 others. A second locus for Aicardi-Goutieres syndrome at chromosome 13q14-21. J. Med. Genet. 43: 444-450, 2006. [PubMed: 15908569] [Full Text: https://doi.org/10.1136/jmg.2005.031880]
Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nature Genet. 38: 910-916, 2006. [PubMed: 16845400] [Full Text: https://doi.org/10.1038/ng1842]
Crow, Y. J., Zaki, M. S., Abdel-Hamid, M. S., Abdel-Salam, G., Boespflug-Tanguy, O., Cordeiro, N. J. V., Gleeson, J. G., Gowrinathan, N. R., Laugel, V., Renaldo, F., Rodriguez, D., Livingston, J. H., Rice, G. I. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics 45: 386-391, 2014. [PubMed: 25243380] [Full Text: https://doi.org/10.1055/s-0034-1389161]
Tonduti, D., Izzo, G., D'Arrigo, S. Riva, D., Moroni, I., Zorzi, G., Cavallera, V., Pichiecchio, A., Uggetti, C., Veggiotti, P., Orcesi, S., Chiapparini, L., Parazzini, C. Spontaneous MRI improvement and absence of cerebral calcification in Aicardi-Goutieres syndrome: diagnostic and disease-monitoring implications. Molec. Genet. Metab. 126: 489-494, 2019. [PubMed: 30826161] [Full Text: https://doi.org/10.1016/j.ymgme.2019.02.006]