Bilateral Non-Arteritic Anterior Ischaemic Optic Neuropathy in a Patient with a COL4A2 Mutation

ABSTRACT

Non-arteritic anterior ischaemic optic neuropathy (NAION) is a common cause of vision loss in adults and is thought to be due to compromised perfusion to the optic nerve head. Patients with NAION in one eye are at risk of recurrence in the fellow eye. We report a case of sequential, bilateral NAION in a patient who was found to have a COL4A2 mutation. COL4A2 encodes a subunit of the collagen 4 protein, the major component of the human basement membranes, and has several known cerebrovascular and ocular associations.

Introduction

Non-arteritic anterior ischaemic optic neuropathy (NAION) is the second most common optic neuropathy after glaucoma and is characterised by sudden painless vision loss due to compromised perfusion of the optic nerve head via various vascular mechanisms. When one eye is affected, there is a risk of contralateral involvement. Up to 15% of patients develop NAION in the fellow eye 5 years after the initial diagnosis.¹ In addition to showing a predisposition in white Caucasians, men, and those over the age of 50,² NAION has several known genetic associations including GP1ab polymorphisms, and familial mitochondrial mutations.^3–6 We report a case of sequential bilateral NAION in a man who was subsequently found to have a COL4A2 mutation, the gene encoding for the collagen alpha-2 chain, one of the six subunits of type IV collagen. Type IV collagen is a major structural component of human basement membranes including those of the cerebral vasculature. Familial mutations may be associated with porencephaly, childhood cerebral haemorrhage, leukoaraiosis, sporadic adult intracerebral haemorrhage, and other manifestations.⁷

Case report

A 65-year-old man with a history of hypertension (HTN), hyperlipidaemia, migraine, obstructive sleep apnoea, high myopia since adolescence, and deep vein thrombosis initially presented reporting vision loss in his right eye and an atypical headache described as a pressure behind the right eye. Visual acuity was 20/50 in the right eye (OD) and 20/20 in the left eye (OS). There was a right relative afferent pupillary defect (RAPD), right optic disc oedema, and a small cup-to-disc ratio in the left eye. The following diagnostic tests were unremarkable: magnetic resonance imaging (MRI) of the brain and orbits, and infectious and autoimmune testing. Based on the clinical neuro-ophthalmological findings and unremarkable test results, he was diagnosed with NAION and treated with a 5-day course of intravenous (IV) methylprednisolone.

The following year, he suffered two retinal detachments in the right eye, but it was not clear if his vision had changed. His vision remained unchanged from an ophthalmological standpoint for the next 5 years until he had epiretinal surgery in the left eye. Several months postoperatively he presented with blurry vision in the left eye and was found to have a visual acuity of hand motion OD and 20/80 OS with refraction and left optic disc oedema. He then had a ground-level fall, immediately after which he experienced worsening of vision in the left eye. Repeated evaluation showed visual acuity consistent with finger counting OD, and 20/400 with eccentric fixation OS. His pupils were equal in size with an RAPD OD and visual field constriction bilaterally. Funduscopic examination showed pallor of the right optic disc and oedema of the left optic disc. MRI of the orbits was unremarkable. A cerebrospinal fluid analysis found no white blood cells, a normal glucose level, an elevated protein level (59 mg/dL), and unremarkable cytometry. Anti-ribonucleoproteins antibodies were present; however, no further diagnostic study was advised after a rheumatology consultation. He was treated with 3 days of IV methylprednisolone. Twenty-four-hour ambulatory blood pressure monitoring showed blood pressure below 130/80 mmHg during the day with night-time drops of his systolic blood pressure into the 80s. After discharge, whole exome and mitochondrial testing was carried out, and a heterozygous COL4A2 mutation was discovered (Variant: c.3421 C > T p. R1141x).

Discussion

Type IV collagen is the primary collagen component of cellular basement membranes and the extracellular matrix that anchors cells and tissues. It performs a complex role as a signalling pathway regulator. The human genes COL4A1 through COL4A6 encode six chains that assemble into collagen IV molecules. Heterotrimers composed of Col4α1 and Col4α2 constitute the majority component of most basement membranes.⁸ Mutations in the COL4A1 and COL4A2 genes can contribute to several neurological diseases, such as myopathy, epilepsy, and glaucoma.⁸ Meta-analyses have also indicated an association between variations in the COL4A2 gene, symptomatic small vessel disease, and deep intracerebral haemorrhage.⁹

The ophthalmic artery is usually the first major intradural branch of the internal carotid artery supplying the structures of the orbit including the optic nerve but may have an anomalous origin from the anterior cerebral artery in an estimated 2–3% of cases and be associated with decreased thickness of the tunica media and adventitia.¹⁰ Computed tomography angiography showed the ophthalmic artery originating from the internal carotid artery in our patient, thus this was not an anomalous origin and was not a contributory factor.

The integrity of ocular structures is essential for the correct operation of the eye and ocular basement membranes in its function to support the cornea, lens, retina, and retinal vasculature. Perturbations in this matrix, and specifically collagen IV, have established ocular disease associations such as Alport’s syndrome, caused by mutations in the COL4A3, COL4A4, and COL4A5 genes and resulting in lenticonus of the anterior lens capsule and retinopathy.^11–14 Mutations in COL4A1 and COL4A2 can result in developmental defects in the eye and brain including the Axenfeld Rieger anomaly.⁷ Mice with COL4A1 or COL4A2 mutations also produce characteristics of ocular anterior dysgenesis that resemble human phenotypes.¹⁵ In mice, ocular development starts around mid-embryogenesis and major ocular structures and ocular basement membranes are formed by birth.¹⁶ Other studies of COL4A2 mutations have suggested that mutations result in the retention of COL4A1 and COL4A2 in the endoplasmic reticulum where prolonged stress can produce negative consequences including cell death.¹⁷ In a seminal report, Gould et al. showed that the phenotype resulting from the COL4A1 mutation could vary substantially among mice such that retinal arteriolar tortuosity and ocular anterior segment dysgenesis may be highly penetrant depending on the underlying genetic background.¹⁸ Our patient did not show features of porencephaly, seizures, cerebral haemorrhage, lacunar stroke, or signs of anterior dysgenesis but did have high myopia, which has been reported in some patients with anterior dysgenesis and COL4A1 mutations.¹⁹ In this case, we suspect that ophthalmic artery collagen may also be subject to structural and functional changes leading to alterations of the basement membrane and adventitia and the occurrence of NAION.

Finally, in our case, lumbar puncture and genetic testing were carried out prior to referral to our centre, and steroids were administered. However, such diagnostic testing and therapy are not, respectively, and routinely recommended for such patients.

Conclusion

The evidence for collagen IV-related ocular dysfunction is plentiful and COL4A2 mutations continue to be associated with new disease entities. Thus, though NAION is a common entity and sequential NAION is a known phenomenon, an association between the mutation and the disease course should be considered in these patients. A mutation affecting the basement membrane integrity or functioning may have been the cause or may predispose to the development of NAION. Although genetic testing is not routinely pursued in the workup of NAION, genetic thrombophilic defects have previously been described as potential aetiologies and other evidence exists for potential genetic aetiologies that may prompt genetic testing in future cases.^17,20–22 In such cases, it may be prudent to test for a COL4A2 mutation, although targeted treatment for this mutation does not currently exist. Gene therapy is a potential future discovery and treatment. If future associations with NAION are found, this case may represent an expansion of the phenotype of COL4A2 mutations.

Funding Statement

The authors reported that there is no funding associated with the work featured in this article.

DisclosureDeclaration of interest statement

No potential conflict of interest was reported by the authors.