Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV) is a rare ocular inflammatory disease that progresses slowly over decades and leads to severe visual impairment. It is classified under ICD-10 as H35.2 (other proliferative retinopathy) and has an OMIM code of 193235.
ADNIV was first reported in 1990 when a family spanning six generations was found to have similar clinical and pathological findings. To date, three independent families have been genetically confirmed to have ADNIV. All reported families are of northern European ancestry, with no gender bias. There are also case reports of de novo mutations causing ADNIV in children.
Chromosomal linkage analysis of the first reported family (34 affected out of 116 members) revealed dysfunction of the CAPN5 gene located on chromosome 11q13. CAPN5 encodes calpain 5, an intracellular calcium-activated cysteine protease.
Two different missense mutations have been discovered, both located in the catalytic domain (exon 6) of the enzyme.
Subsequently, three additional mutations in the CAPN5 gene have been described, two affecting the catalytic domain and one affecting the regulatory domain.
To date, only three families worldwide have been genetically confirmed, making it an extremely rare disease. However, there may be undiagnosed mild cases or cases with incomplete penetrance. Genetic testing of the CAPN5 gene is necessary for a definitive diagnosis, and referral to a specialized facility is appropriate when further evaluation for similar symptoms is needed.
In the early stages of ADNIV, symptoms are scarce. The main symptoms are as follows.
ADNIV is classified into five distinct chronological stages, each lasting approximately 10 years. Onset occurs between the ages of 10 and 30.
Stages 1-2 (Inflammation and Degeneration)
Stage 1: Mild cellular infiltration in the anterior and posterior chambers. Electroretinography shows attenuation of the dark-adapted b-wave amplitude.
Stage 2: Moderate cellular infiltration in the anterior and posterior chambers, cataract (usually PSC), and retinal pigment changes and degeneration. Electroretinography shows flattening of the dark-adapted b-wave.
Stage 3-5 (Proliferative/Terminal)
Stage 3: Progression of PSC, formation of anterior subcapsular cataract (ASC), iris synechiae. Electroretinogram shows attenuation of dark-adapted a-wave amplitude.
Stage 4: Peripheral anterior synechiae (PAS), angle-closure glaucoma, neovascular glaucoma, tractional retinal detachment (TRD), vitreous hemorrhage (VH). ERG is non-recordable.
Stage 5: No light perception (NLP), phthisis bulbi.
ADNIV is caused by gain-of-function mutations in the CAPN5 gene. The mutant protease has a lower calcium threshold for activation, leading to sustained overactivation of CAPN5, which results in multiple intracellular effects such as apoptosis, cell migration, and intracellular signaling.
Clinicopathological studies support an immune-mediated component. Histopathology of affected eyes shows T-cell infiltration (CD4+ and CD8+ cells) into ocular tissues without evidence of systemic inflammatory disease, suggesting that an eye-limited immune process may contribute to chronic intraocular inflammation.
The diagnosis of ADNIV is based on ophthalmic examination findings, family history, and functional abnormalities detected by electroretinography. A definitive diagnosis is made by genetic analysis demonstrating a mutation in the CAPN5 gene.
Since nearly all patients have an affected first-degree relative, a detailed assessment of the patient’s family history is essential for diagnosis. ADNIV patients characteristically present with vision loss after the age of 40, although subtle signs from earlier stages may have been overlooked.
The youngest symptomatic patient reported was a 16-year-old with vitreous hemorrhage (VH) from peripheral neovascularization. In one cohort, nine children under 14 years of age were examined, but none showed symptoms or electroretinographic changes.
Electroretinogram findings vary depending on the disease stage, similar to clinical findings.
With an appropriate clinical context, laboratory tests are not essential for diagnosis. They are primarily used to rule out other etiologies when there is no family history or when genetic test results are unavailable.
Differential diagnosis varies depending on the stage of the disease.
Treatment of ADNIV is challenging and must be individualized based on the specific signs observed. Despite best efforts, the disease relentlessly progresses and typically leads to phthisis bulbi.
In the early stages, the focus is on controlling inflammation and cystoid macular edema, with topical, periocular, and intravitreal corticosteroid administration. Most patients with ADNIV eventually become resistant to conventional steroid-based immunosuppression.
Fluocinolone acetonide (FA) implant: Retisert (Bausch & Lomb) has been used successfully, typically introduced at stage 4 of the disease, although success at stages 2 and 3 has also been reported. A review of 9 eyes showed complete resolution of inflammation, regression of neovascularization, and improvement of cystoid macular edema. However, it did not prevent vision loss, and 3/7 eyes required surgical intervention for intraocular pressure reduction.
Anti-VEGF therapy: Intravitreal administration of anti-VEGF agents is used for the treatment of cystoid macular edema, but efficacy is limited.
Laser photocoagulation: Used for the treatment of peripheral neovascularization, but results regarding stabilization of neovascularization are mixed.
Elevated intraocular pressure is a common late finding in ADNIV, usually secondary to steroid response, pupillary block, secondary angle closure due to fibrosis, or uveitic glaucoma. In a study of 5 patients (9 eyes) with ADNIV and secondary glaucoma, 5 eyes required Ahmed glaucoma valve surgery even after FA implantation.
Similar to other autosomal dominant disorders, mutations in the CAPN5 gene cause a gain-of-function of the protease. A lowered calcium activation threshold leads to sustained overactivation of CAPN5, resulting in the following intracellular effects:
Analysis of abnormal gene regulation in a mouse model of ADNIV has revealed that CAPN5 overactivation is associated with abnormal synaptic function in the outer plexiform layer. Interestingly, knockout of the CAPN5 gene in mice does not cause pathology.
Histopathology of affected eyes shows T-cell infiltration (CD4+ and CD8+ cells) into ocular tissues without evidence of systemic inflammatory disease or consistent circulating anti-retinal antibodies. It is suggested that an eye-limited immune process may contribute to chronic intraocular inflammation and subsequent proliferative complications.
Recently, mutations in the regulatory domain have been discovered, which resulted in milder clinical manifestations. The specific downstream signaling pathways activated to generate the ADNIV phenotype are currently not well understood and require further investigation.
ADNIV is caused by gain-of-function mutations in CAPN5, so treatment strategies may ultimately require suppression or editing of the mutant allele.
A non-specific calpain inhibitor (SJA6017) has been developed and shown to reduce retinal damage in hypoxic retinal diseases, but its use in ADNIV patients has not been studied. Since calpastatin, an endogenous calpain inhibitor, does not bind to CAPN5, it is predicted that binding to SJA6017 is also poor.
Gene replacement therapy has been successfully tested in recessive retinal diseases with loss-of-function mutations, but dominant gain-of-function mutations require a different approach. If attempts to repair gain-of-function mutations in retinitis pigmentosa succeed, it may pave the way for suppressive therapy in ADNIV patients.
The prognosis of untreated or inadequately treated ADNIV is extremely poor. It has been found that 35% of patients over 60 years old have no light perception (NLP), and an additional 30% have visual acuity of 20/800 (0.025) or worse. Even with aggressive treatment, disease progression cannot be completely halted, but treatment may slow progression and help maintain some visual function.
