Recommended panel testing at Breda Genetics for Aicardi-Goutières syndrome:
Aicardi-Goutières syndrome (ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, TREX1)
Summary
Aicardi-Goutières (AGS) syndrome is an extremely rare pathology that mainly affects the brain, the immune system, and the skin. At birth, signs and symptoms of the disorder are mostly absent as onset is usually in the first year of life. In approximately 20% of patient there is a combination of thrombocytopenia, elevated blood levels of liver enzymes, hepatosplenomegaly and abnormal neurological responses at birth. The combination of these symptoms is associated with the response of the immune system to congenital viral infections, although no actual infection can be diagnosed in the patients. Therefore Aicardi-Goutières (AGS) syndrome is sometimes referred to as a “mimic of congenital infection.” Aicardi-Goutières syndrome is mostly inherited in an autosomal recessive fashion. Rarely, it shows an autosomal dominant inheritance pattern with possible de novo mutations (this is more typical when there is no family history of the disorder).
Detailed clinical description
Aicardi-Goutières syndrome is a progressive encephalopathy usually characterized by basal ganglia calcifications, acquired microcephaly, chronic lymphocytosis in the cerebrospinal fluid, white matter abnormalities, and raised interferon-alpha. Due to severe neurological problems most cases do not survive after the childhood. However individuals with milder neurological problems and later onset may live into adulthood.
- Feeding problems are described as, during encephalopathy, affected babies do not feed well and are usually irritable.
- Patients may show developmental regression.
- Brain and skull growth is slowed down.
- Tissue damage and inflammation can be seen in the central nervous system.
- Calcifications (abnormal deposits of calcium) and leukodystrophy (deterioration of white matter) are also typical cerebral findings.
- Intellectual disability can be profound.
- Neuromuscular problems may appear such as involuntary tensing of various muscles, muscle stiffness, and weak muscle tone in the trunk.
- The skin may be itchy and painful on ears, fingers and toes.
- Another typical sign of Aicardi-Goutières syndrome is chilblains, which are puffy and red lesions, caused by inflammation of small blood vessels.
- Joint stiffness, mouth ulcers and vision problems may also occur in this disorder as well as sterile pyrexias and hepatosplenomegaly.
Prevalence
Aicardi-Goutières syndrome is a rare disorder. Its exact prevalence is unknown because of its extremely rare pathology.
Molecular Genetics
Aicardi-Goutieres syndrome is a genetically heterogeneous disorder. It has so far been associated with mutations in the following genes: ADAR, TREX1, RNASEH2A, RNASEH2B, RNASEH2B, IFIH1 and SAMHD1.
The RNASEH2A, RNASEH2B, and RNASEH2C, TREX1 genes provide instructions for making nucleases. Nucleases are enzymes that help break up molecules of DNA and RNA. Mutations in these genes result in the accumulation of unneeded DNA and RNA in cells. DNA and RNA which is unneeded may be mistaken by cells for that of viral invaders. This triggers immune system reactions, which results in signs and symptoms of Aicardi-Goutières syndrome.
Differential diagnosis
The genetic differential diagnosis of Aicardi-Goutieres syndrome includes the following:
- Cerebroretinal microangiopathy with calcifications and cysts.
- Labrune syndrome (leukoencephalopathy, brain calcifications, and cysts).
- 3-hydroxyisobutyric aciduria (microcephaly, dysmorphic facial features, congenital intracerebral calcification and migrational brain disorder).
- mitochondrial cytopathies (including Leigh syndrome and familial mitochondrial encephalopathy with intracerebral calcifications)
- Hoyeraal-Hreidarsson syndrome, a severe form of dyskeratosis congenital, which is caused by mutation in DKC1 or TINF2.
- classic Cockayne syndrome
- band-like calcification polymicrogyria
- microcephaly-intracranial calcification syndrome (MICS – it is likely that most cases of MICS are in fact AGS). A number of other phenotypes are associated with neonatal intracranial calcification. So the differential diagnosis is even wider.
- Among non-genetic causes TORCH congenital infections are the most common and important conditions to rule out.
Genetic Testing
Molecular testing approaches may be done by serial single-gene testing, although multi-gene panel testing based on next generation sequencing is certainly faster and more convenient. If only one pathogenic variant is identified in RNASEH2A, RNASEH2B, RNASEH2C, or SAMHD1, gene-targeted deletion/duplication analysis can be considered next. Gene-targeted deletion/duplication analysis may also be considered if a heterozygous pathogenic variant that is not known to be associated with autosomal dominant AGS is identified in TREX1 or ADAR.
Recommended panel testing at Breda Genetics for Aicardi-Goutières syndrome:
Aicardi-Goutières syndrome (ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, TREX1)
References:
Aicardi-Goutières syndrome is caused by IFIH1 mutations. Oda H, Nakagawa K, Abe J, Awaya T, Funabiki M, Hijikata A, Nishikomori R, Funatsuka M, Ohshima Y, Sugawara Y, Yasumi T, Kato H, Shirai T, Ohara O, Fujita T, Heike T. Am J Hum Genet. 2014 Jul 3;95(1):121-5. PMID 24995871
Aicardi-Goutières syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Crow YJ, Rehwinkel J. Hum Mol Genet. 2009 Oct 15;18(R2):R130-6. PMID 19808788
The neonatal form of Aicardi-Goutières syndrome masquerading as congenital infection. Jepps H, Seal S, Hattingh L, Crow YJ. Early Hum Dev. 2008 Dec;84(12):783-5. PMID 18829186
