Isolated optic neuropathy due to folate deficiency with associated iron overload

Abstract

Isolated optic neuropathy due to folate deficiency is rarely reported. Poor dietary practices, malabsorption, and tobacco/alcohol abuse are usually responsible. We examined a patient with blinding optic neuropathies and isolated folic acid deficiency. Visual acuity recovered after folate replacement. At the same time, serological investigation revealed high ferritin and iron saturation levels with negative genetic markers for haemochromatosis consistent with the diagnosis of iron overload syndrome. There are no reports of blindness associated with iron overload syndrome.

Background

Folate deficiency is a rare cause of optic neuropathy usually due to poor dietary practices, malabsorption or tobacco/alcohol use.¹ Optic neuropathy as a result of folate deficiency is believed to result from diminished production of dihydrofolate crucial for the elimination of formate.² Elevated formate can alter the mitochondrial competency for oxidative phosphorylation and lead to an accumulation of free radicals. The unmyelinated axons in the optic nerve are particularly susceptible to damage from oxidative species. Folate is also integral to the methionine cycle and thus, necessary for amino acid production. Undetected, folic acid deficiency can lead to significant vision loss. Deficiency in a population of young women poses a particular risk for tube closure failure, a condition generally seen in B₁₂ deficiency.

Case presentation

A 38-year-old woman noted progressive painless bilateral visual loss over 7 weeks. She lost the ability to read and drive. Throbbing, aching discomfort in both legs developed concurrently. History revealed no previous visual or haematologic symptoms. The patient was a modest drinker without any gastrointestinal (GI) disorder, dietary fetish or weight loss. General neurological examination was unremarkable. Visual acuity was 20/200 right eye (OD) and 20/80 left eye (OS). Pupils were sluggish without afferent defect. Colour vision was 0/6 both eyes (OU) (HRR colour plates). Viewing Amsler’s grid demonstrated no metamorphopsia. Funduscopic examination showed normal-appearing optic disc with full nerve fibre bundles confirmed by optical coherence tomography sera spectral. Humphrey’s 24/2 visual fields showed in both eyes cecocentral scotoma with associated relative superior and inferior arcuate bundle fibre defects (figure 1). Laboratory results showed haemoglobin 1.65 g/L; haematocrit 51%; mean corpuscular volume 123.2 (normal=80–100); aspartate aminotransferase 104 U/L (normal=10–30); alanine aminotransferase 114 U/L (normal=6–29), bilirubin 0.2 (normal ≤1.2) and alkaline phosphatase 68 U/L (normal=40.0–156.0). Folate acid levels repeatedly were 1.9 ng/mL (normal ≥5.4). Ferritin of 551 (normal=10–291.0), with 94% iron saturation (normal=20%–55%). Genetic testing was negative for both Hemochromatosis (HFE) gene and Janus Kinase 2 (JAK2). Abdominal ultrasound revealed liver heterogeneity and fatty infiltrate.

Figure 1.

The 24–2 visual field showing in both eyes cecocentral scotoma with associated relative superior and inferior arcuate bundle fibre defects.

Differential diagnosis

Common causes of acquired optic neuropathy are demyelinating diseases, such as multiple sclerosis, autoimmune diseases, such as myelin oligodendrocyte glycoprotein (MOG) and neuromyelitis optica (NMO) spectrum disorders, ischaemic events, metabolic dysfunctions, such as vitamin B₁₂ deficiency, ethylene glycol and methanol toxicity, and rarely, genetic conditions, such as Leber’s optic neuropathy. While rare, folate deficiency is an essential consideration in the differential diagnosis of optic neuropathy. In this case, MS and any ischaemic events could be ruled out. Vitamin B₁₂ levels were normal. The patient’s laboratory work suggested a deficiency in folate acid with a level significantly below the normal range. Ferritin and iron saturation were uncharacteristically high at 551% and 94%, respectively. A diagnosis of optic neuropathy due to folate acid deficiency was made.

Outcome and follow-up

High-dose oral folic acid was administered with significant improvement in visual acuity at 2 months (20/40 OS and 20/80 OD). At 1 year, visual acuity recovered to 20/25 OU, with improved visual fields (figure 2) and some restoration of colour vision (3.5/6 HRR OU). Iron overload was corrected after the patient was treated empirically with biweekly phlebotomy. Follow-up blood work demonstrated ferritin of 19 and iron saturation to 27%, and the patient reported a resolution of lower extremity aching. The patient no longer needed folic acid supplements after biweekly phlebotomy.

Figure 2.

Resolution of the field defects after supplementation with folic acid.

Discussion

Isolated optic neuropathies due to folic acid deficiencies are rare. A patient with isolated folic acid deficiency who altered her diet during a period of clinical depression was reported.³ Visual function was restored with oral supplementation of folic acid and an altered diet.³ Golnik and Schaible demonstrated that folic acid supplementation improved visual function in patients with folic acid deficiency and progressive bilateral optic neuropathy.⁴ Out of a population of five patients, the average improvement in visual acuity was five lines over the course of 2 months.³ Folic acid deficiency is generally due to poor diet, GI disorders or alcohol abuse. Our patient had none of these problems. However, there was evidence of iron overload. The relationship between the two conditions is problematic.

A substantial deposit of iron in the liver might inhibit the conversion of folate to its storage form, N5-methyl-tetrahydrofolic acid.⁴ It was hypothesised that haemochromatosis causes folic acid deficiency by potentially two mechanisms: plausibly haemosiderin-laden intestinal mucosa affects folic acid absorption.⁵ Alternatively, it is plausible that folic acid deficiency is not the result, but rather the cause of iron overload. Folate deficiency inhibits methionine synthesis—low levels of methionine results in liver malfunction through fat accumulation.⁵ In the event of pre-existing liver damage, iron overload may occur rapidly throughout the body.⁵

The case is unique in that folate deficiency developed in isolation and was unrelated to previously reported commonly associated pathologies. The body has no dedicated mechanism for iron excretion; therefore, it is rapidly stored. The deposition of iron in macrophages can result in liver damage. Conversely, liver damage can instigate iron overload as a result of reduced production of hepcidin, a regulator of iron absorption. Which comes first is still debatable, and any causative interaction between folate deficiency and iron overload syndrome is not understood. It is likely that folate deficiency can produce an indirect thiamine deficiency, which could be a clinical manifestation seen in folate-deficient optic neuropathy.⁶ The mechanism of action stems from a deficient dihydrofolate reductase activity, essential to convert thiamine into its active form, thiamine pyrophosphate.⁷ It would be beneficial to provide a combined administration of folic acid and thiamine to enhance the patients recovery. We treated a patient presenting with isolated optic neuropathy proved secondary to folic acid deficiency. However, there are no reported cases of iron overload syndrome causing optic neuropathy.

Learning points.

• Offers new evidence as to a previously unreported relationship between folate deficiency and iron overload syndrome.

• A unique case in which a patient presented with folic acid deficiency without history of alcoholism or malabsorption.

• Clinicians should consider abdominal ultrasound and careful haematological evaluation should always be part of the workup to rule out iron overload as an outcome to symptoms in optic neuropathies.

Ethics statements

Patient consent for publication

Obtained.