Immunogenetic diseases are a group of disorders characterized by genetic mutations that cause primary immunodeficiency. They present with a wide variety of systemic and ocular symptoms. Among these, Aicardi-Goutières syndrome (AGS) and Singleton-Merten syndrome (SGMRT) are known to be associated with glaucoma.
Both are rare diseases caused by mutations in genes involved in innate immunity. In the EGS classification, they are categorized as glaucoma associated with non-acquired systemic diseases or syndromes 1). In syndromic glaucoma, molecular diagnosis contributes to the revision of clinical diagnosis and appropriate genetic counseling 2).
SGMRT has a higher penetrance of glaucoma. In patients with DDX58 mutations, 94% develop glaucoma. In contrast, in AGS, it is reported to be over 20% with SAMHD1 mutations, varying greatly depending on the mutated gene.
In AGS, neurological symptoms appear within the first year of life. In SGMRT, in addition to osteoarticular and skin symptoms, elevated intraocular pressure is observed from childhood.
Features of AGS
Systemic findings: Progressive encephalopathy, microcephaly, leukodystrophy, cerebral atrophy, intracranial calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, hepatosplenomegaly, thrombocytopenia, lupus-like syndrome.
Ocular findings: Congenital or acquired glaucoma (often diagnosed within 6 months of birth), optic atrophy, cortical blindness.
Differential diagnosis: May be misdiagnosed as TORCH syndrome.
Features of SGMRT
Systemic findings: Psoriasiform rash, calcification of the aorta and heart valves, osteopenia/osteoporosis, tendon rupture, arthritis, dental abnormalities.
Ocular findings: Congenital or juvenile open-angle glaucoma (median age at diagnosis 5 years). Glaucoma is the most penetrant feature in SGMRT.
Corneal findings: High incidence of corneal graft failure.
Seven genes are known to be associated with AGS. Most are inherited in an autosomal recessive pattern, but IFIH1 mutations can be autosomal dominant.
| Gene | Inheritance | Glaucoma risk |
|---|---|---|
| SAMHD1 | AR | Highest (>20%) |
| TREX1 | AR | Reported |
| RNASEH2A/B/C | AR | Reported |
| ADAR | AR | Lowest |
| IFIH1 | AD | Lowest |
SGMRT is a rare autosomal dominant disorder associated with mutations in the DDX58 and IFIH1 genes, which are involved in innate immunity.
Genetic testing is important for a definitive diagnosis of glaucoma associated with immune-mediated genetic disorders. Targeted gene testing or exome/genome sequencing is used2).
Advantages of molecular diagnosis:
Follows general examination methods for childhood glaucoma1).
Glaucoma treatment in AGS and SGMRT involves medication, and surgical intervention is considered as needed.
Intraocular pressure is managed with glaucoma eye drops (beta-blockers, carbonic anhydrase inhibitors, oral carbonic anhydrase inhibitors, etc.).
In pediatric glaucoma, initial surgery is indicated in almost all cases. Drug therapy is often neither effective nor feasible in the long term 1).
Visual prognosis in patients with AGS and SGMRT is poor, and multiple glaucoma surgeries may be required.
The basic treatment strategy (medication followed by surgery) is similar to that for ordinary pediatric glaucoma, but the visual prognosis is poorer and multiple surgeries are often required. In SGMRT, systemic treatment with JAK inhibitors may also be effective for ocular symptoms, and a different approach from standard glaucoma treatment is being considered.
The core pathogenesis of glaucoma associated with SGMRT is dysfunction of the RIG-I (retinoic acid-inducible gene I) receptor due to DDX58 gene mutation.
The RIG-I receptor is an important component of innate immunity and is also present in trabecular meshwork cells. Dysfunction of the RIG-I receptor due to DDX58 mutation causes glaucoma through the following pathways:
The RIG-I receptor is also present in the cornea. Due to dysfunction of the corneal RIG-I receptor, SGMRT patients have a high incidence of corneal graft failure. This should be considered when planning corneal surgery.
In AGS, mutations in genes involved in innate immunity (TREX1, RNASEH2A/B/C, SAMHD1, ADAR, IFIH1) cause abnormal activation of the type I interferon pathway. This chronic immune activation leads to systemic inflammation and tissue damage, but the detailed mechanism of glaucoma development in ocular tissues has not yet been fully elucidated.
Mutations in DDX58, the causative gene for SGMRT, lead to dysfunction of the RIG-I receptor. This RIG-I receptor is also present in the cornea, and its functional abnormality is thought to contribute to the high incidence of corneal transplant failure.
Janus kinase (JAK) inhibitors have shown promising results in the systemic treatment of SGMRT. They may also demonstrate efficacy in treating ocular symptoms of this disease, and future research is anticipated.
Similar to inherited retinal diseases, gene-specific therapeutic approaches may become possible for glaucoma in the future. The importance of molecular diagnosis is increasingly emphasized from the perspective of precision medicine 2).
In glaucoma associated with immune-mediated genetic diseases, identification of the causative gene directly leads to the identification of therapeutic targets. In particular, development of therapies targeting the RIG-I receptor pathway is expected.
