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REVIEW ARTICLE
Folic acid deficiency and vision: a review
Ouafa Sijilmassi1,2
Received: 27 November 2018 /Revised: 10 February 2019 /Accepted: 20 March 2019 /Published online: 27 March 2019
# Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Folic acid (FA), also termed folate, is an essential vitamin for health at all ages since it participates in the biosynthesis of
nucleotides, amino acids, neurotransmitters, and certain vitamins. It is therefore crucial for rapidly growing tissues such as those
of the fetus. It is becoming clear that FA deficiency and impaired folate pathways are implicated in many diseases of both early
life and old age. FA can be transported into the cell by the folate receptor, the reduced folate transporter, and proton-coupled folate
transporter. Folate transport proteins are present in certain eye tissues, which explains why FA plays an important role in eye
development. The purpose of this literature review is to investigate the evidence relating FA deficiency to eye diseases.
Keywords Folic acid deficiency . Folate receptors . Eye disease
Introduction
Folic acid (FA), also known as folate (in its naturally occurring
state) and vitamin B9, is a water-soluble vitamin considered
essential for women who may be pregnant. Since this vitamin
cannot be synthesized by the human body, it must be obtained
either through the diet or from supplementation [1]. The dif-
ference between folate and FA is that, unlike folate, FA is not
naturally present in foods but is produced synthetically for use
in food fortification and dietary supplementation. In general,
FA is the most common form of folate used as a nutritional
supplement.
Folate can be found in many natural foods, such as le-
gumes, yeast, fruit, and leafy green vegetables [2]. It is also
present in some animal foods, such as liver and kidney.
However, some of the folate in natural foods may be destroyed
during the cooking process, especially with high temperatures
and prolonged cooking times [3].
During pregnancy, the requirement for FA increases
and it becomes crucial for both the mother’s health and
fetal development. A daily FA supplement (400 mcg/
day) should be taken during the first trimester of preg-
nancy [4].
Many published studies have examined the effect of
low folate status on the health of offspring, both before
and during gestation. These show that low levels of folate
are associated with several birth defects, such as neural
tube defects (especially anencephaly and spina bifida) [5,
6], low infant birth weight [7], and cleft palate [8].
Studies have shown that the periconceptional administra-
tion of FA helps prevent the occurrence and recurrence of
many congenital abnormalities [9], especially those relat-
ed to the neural tube, which forms the embryonic nervous
system. FA deficiency not only affects fetal growth and
development, it is also known that a poor folate status is a
risk factor for age-related cognitive decline and impair-
ment in the elderly. In fact, low folate status is associated
with cognitive dysfunction in aging [10], maybe because
most adults do not consume enough quantities of FA or
by inadequate ingestion, absorption, or destruction of the
vitamin. For this reason, the aim of this paper is to review
the impact of FA deficiency on eyes from both embryonic
development and in adulthood.
A brief description of human eye
development
In vertebrates, the development of the nervous system and the
eye are closely related. The eye is a complex organ that is
* Ouafa Sijilmassi
o.sijilmassi@ucm.es
1 Faculty of Optics and Optometry, Department of Anatomy and
Human Embryology, Universidad Complutense de Madrid, Avda.
Arcos de Jalón, 118, 28037 Madrid, Spain
2 Faculty of Optics and Optometry, Department of Optics, Universidad
Complutense de Madrid, Avda. Arcos de Jalón, 118,
28037 Madrid, Spain
Graefe's Archive for Clinical and Experimental Ophthalmology (2019) 257:1573–1580
https://doi.org/10.1007/s00417-019-04304-3
http://crossmark.crossref.org/dialog/?doi=10.1007/s00417-019-04304-3&domain=pdf
http://orcid.org/0000-0003-0513-0229
mailto:o.sijilmassi@ucm.es
actually considered to be an extension of the brain [11]. In the
human embryo, the eye begins to develop around day 22 of
gestation. At this stage, the diencephalon protrudes on either
side as two lateral outgrowths forming the optic vesicle. On
day 27, the optic vesicles come into contact with the adjoining
surface ectoderm, which thickens to form the lens placode. At
the same time, the distal part of the optic vesicle is invaginated
into its more proximal part to form a double-layered optic cup:
the inner and the outer layers. The sensory retina, inner non-
pigmented ciliary body epithelium, and posterior iris epitheli-
um are derived from the inner layer of the optic cup, while the
retinal pigmented epithelium, outer pigmented epithelium of
the ciliary body, and anterior iris epithelium are differentiated
from the outer layer [12].
By day 36, in parallel with the development of the optic
cup, the lens vesicle is formed and detaches from the surface
ectoderm [13]. At around the time the lens vesicle separates
from the surface ectoderm, the ectodermal layer in this region
forms the future corneal epithelium. During this period, a fail-
ure of the lens vesicle to separate from the surface ectoderm
results in lenticulocorneal fusion [14].
Between weeks 4 and 6, the neural retina is composed of
two zones: the inner and outer neuroblastic layers. The first
layer is differentiated to form the ganglion, Müller, and
amacrine cells. The outer neuroblastic cell layer, however, will
differentiate into photoreceptor, bipolar, and horizontal cells
[12]. A failure of organization or delayed differentiation of the
neuroblastic cells during development leads to retinal dyspla-
sia [14].
The first evidence of vitreous formation is present during
the third to fourth week [15]. By the end of the sixth week, the
hyaloid vessels and associated mesenchyme situated at the
center of the optic stalk have developed into arteries and veins
[16].
During the third month, the pupillary membrane becomes
fully formed. By the end of the third month, the lip of the optic
cup begins to elongate. The region of the outer layer of the
optic cup becomes the anterior iris epithelium and outer
pigmented epithelium of the ciliary body, while the inner layer
forms the posterior iris epithelium and inner non-pigmented
epithelium of the ciliary body [12]. At this period, a secondary
vitreous composed of fine fibrillar material becomes evident,
and completely encloses the primary vitreous [17]. By the fifth
month, the sclera is differentiated [18].
The choriocapillaris starts to differentiate during the
fourth and fifth week. By the fifteenth week, the first
choroidal arterioles and veins can be seen; arteries and
veins become distinguishable at the 22nd week [19]. By
the sixth week, the innermost layer of the choroid, or
Bruch’s membrane, begins to develop. Bruch’s mem-
brane partly regulates the reciprocal exchange of bio-
molecules, nutrients, and oxygen between the retina
and the general circulation [20].
Folate transport proteins and their
localization in ocular structure
folate transport proteins The essential role of the folate me-
tabolism in cellular biochemistry is to provide one-carbon
building blocks for the synthesis of purines and pyrimidine.
These building blocks are needed for DNA and RNA synthe-
ses [21]. Folate and its one-carbon derivatives cannot pene-
trate biological membranes by simple diffusion. For this rea-
son, they use three different transport processes to enter cells:
folate receptor (FR), reduced folate transporter (RFT-1), and
proton-coupled folate transporter (PCFT) [22–25].
The folate receptor (FR), also known as folate-binding pro-
teins (Folbps) in mice, is expressed at the cell surface. In
humans, there are four FR isoforms (α, β, γ, and δ), all of
them are tissue-specific [26]. On the other hand, in the mouse,three Folbps have been identified: Folbp1 and Folbp2 which
are homologs of FR-α and FR-β, respectively, and Flobp3 is
homolog of FR-δ [27].
In general, FRα, also known as folate receptor 1 (Folr1), is
a glycoprotein attached to the apical cell membrane of normal
epithelial cells [28] which is expressed in limited healthy ep-
ithelial cells. It provides the mechanism for the cellular uptake
of folate from the blood and binds folate at a high affinity to
mediate transport into the cell cytoplasm [29].
FRβ or Folr2, is the most common folate receptor and can
be localized on the surface of most cells. Its expression is
higher in both fetal cells and the nervous system [30]. FRβ
is present especially in the placenta and activated macro-
phages [31, 32]. Folr2 is considered as a biomarker for acti-
vated macrophages in autoimmune and inflammatory diseases
[33, 34]. In the eye, macrophages are present in the ocular
tissues [35].
Little has been published about the protein receptor FRγ
and its role in folate transport [36]. It appears that FRγ is
found in hematopoietic tissues and other physiological fluids
[37].
Recent studies on FRδ, also known as folate receptor 4
(Folr4), indicate that it is predominantly expressed in regula-
tory T cells (Treg cells) [38] and may play a role in controlling
immune responses [39]. Yamaguchi et al. [40] found that Treg
cells expressed high amounts of Folr4. The ocular pigment
epithelial cells of the iris, the ciliary body, and the retina con-
tribute to the immune property of the eye [41]. Indeed, the
ocular pigment epithelium possesses the ability to promote
activated T cells to regulatory T cells and then use them as a
tool to establish immune regulation in the eye [42].
Like FRα, the reduced folate transporter-1 protein
(RFT-1) regulates the cellular uptake of molecules in-
side the cell [43]. However, in contrast to FRα, the
expression of RFT-1 is limited to those cells that are
involved in the vectorial transfer of folates from one
side of the cell to the other [24].
1574 Graefes Arch Clin Exp Ophthalmol (2019) 257:1573–1580
Finally, the proton-coupled folate transporter (PCFT) is a
typical integral membrane transporter protein that spans the
membrane 12 times [44]. The PCFT mediates the intestinal
absorption of folates and the transport of folates into the cen-
tral nervous system [45].
Localization in ocular structure FA transport proteins are local-
ized in many eye structures. Numerous studies have shown that
the expression of FRα is ubiquitous in all layers of the retina
[46, 47]. FRα has also been detected in the ganglion cell layer
and in Müller cells [48]. This receptor is also present in the
outer limiting membrane [49]. The outer plexiform layer is also
intensely immunopositive for FRα [47, 49]. On the other hand,
laser scanning confocal microscopy in mice and rats revealed
that FRα mRNA transcripts are expressed in the basolateral
region of the retinal pigment epithelium (RPE), the choroid,
and the neural retina [47, 49]. Several studies have indicated
that the principal role of this receptor is to mediate the uptake of
folate into the different cells of the retina [47, 50]. In addition,
FA is a necessary metabolite for development of the lens, re-
quiring intakes through the FRα receptor [51].
As seen above, FR-β is expressed in the activated macro-
phage. As far as we know, only one study has investigated the
expression of this receptor in the eye [52]. In this study, func-
tional FR-β was detected in activated macrophages in the
retina. FRδ is present in RPE cells. Again, as far as we know,
only one study has investigated the expression of this receptor
in the eye [48].
RFT-1 is distributed in the apical membrane of the RPE
[46, 50]. In a study based on the cellular expression of the
reduced-folate transporter in the retina, Smith et al. [47] have
shown that this receptor mediates the efflux of folate from the
RPE cell into the subretinal space across the apical membrane.
The authors concluded, as have many others, that the expres-
sion of RFT-1 is only limited to the RPE. This epithelium is a
monolayer of cells that mediate the vectorial transport of nu-
trients like folate from choroidal blood to photoreceptor cells
[50, 53].
Expression of the proton-coupled folate transporter (PCFT)
mRNA in the intact human retina was investigated by
Umapathy et al. [54]. All cell layers of the retina express this
transporter. PCFT was detectable in cells in the ganglion cell
layer, the outer limiting membrane, the inner nuclear layer
(which contains the cell bodies of the Müller cells and other
neural cell types, namely, horizontal, bipolar, and amacrine
cells), the inner segments of the photoreceptor cells, and the
RPE cell layer. In 2010, Bozard et al. suggested that the two
proteins PCFT and FRαmay work in coordination to mediate
folate uptake in retinal Müller cells. Retinal Müller cells have
an absolute folate requirement and play a crucial role in sus-
taining the neurons of the retina [49]. Another study indicates
the existence of FRα and PCFT on rabbit corneal epithelial
cells [55].
Figure 1 illustrates a schematic diagram of the structural
organization of the retina.
Folic acid deficiency and ocular disease
FA deficiency in patients
It is known that folate is essential during the early
stages of human development [56]. As previously stat-
ed, the folate requirement is increased during pregnancy,
above all to sustain the demand for rapid cell prolifer-
ation and the growth of fetal maternal tissue, etc. This
vitamin plays an essential role in embryonic develop-
ment, but its importance is not confined to the fetal
period, it is also important for adults. In fact, FA can
enhance growth and repair mechanisms even in adult-
hood [57]. Folate deficiency resulting from diets lacking
in this vitamin can lead to severe complications.
Alterations in folate transport can also have harmful
effects.
Deficient levels of folate have serious consequences for the
visual system. In fact, folate deficiency can lead to nutritional
amblyopia [58], which is typically present with central or
cecocentral scotomas, pallor of the optic disc, optic atrophy
[59], and a gradual decrease in vision, resulting in difficulty
with reading and recognizing faces [60].
FA deficiency also leads to an abnormal accumulation of
homocysteine [21, 59, 61]. Increased retinal homocysteine
induces retinal neuron death, altering the inner and outer ret-
inal layers and affecting the cells of the ganglion cell layer
[62]. Some clinical studies have implicated homocysteine in
maculopathy [63], open-angle glaucoma [64], and diabetic
retinopathy [65].
Lack of folate is also involved in nutritional optic neurop-
athy, which is characterized by damage to the retinal nerve
fiber layer. In a patient diagnosed with folate deficient optic
neuropathy, folate deficiency is presented as a visual abnor-
mality with a 4-week history of progressive visual loss.
Bilateral retrobulbar optic neuropathy was also found to be
present. Investigations revealed severe folate deficiency.
Subsequent correction of the folate levels with oral supple-
mentation improved the patient’s visual acuity [66].
On the other hand, Leber hereditary optic neuropathy
(LHON) is a bilateral optic atrophy leading to the loss of
central vision in which the primary etiological event is a mu-
tation in the mitochondrial DNA [67]. Folate metabolism in
the mitochondria is essential for generating formate [68]. In
2010, the folate gene polymorphisms MTHFR C677T,
A1298C, and MTRR A66G were examined for the first time
by Aleyasin et al. [69] as a possible LHON secondary genetic
risk factor in LHON patients. Results show a strong associa-
tion between LHON syndrome and MTHFR C677T and
Graefes Arch Clin Exp Ophthalmol (2019) 257:1573–1580 1575
MTRR A66G polymorphisms. For the authors, folate gene
polymorphism plays a role in LHON etiology. They suggest
that disruption of the mitochondrial metabolism in conjunc-
tion with folatepathway gene alteration could affect electron
transport, leading to mitochondrial dysfunction and reduced
ATP levels, which may contribute to the severity of LHON
neuropathology.
Folate deficiency is also a possible risk factor for cataracts.
A cross-sectional study has shown that elderly Taiwanese pa-
tients with cataracts had a lower plasma folate level than those
without cataracts, and that folate insufficiencywas significant-
ly associated with cataracts [70]. Similarly, hyperhomocystei-
nemia with low folate levels in older age groups could be a
risk factor for senile cataracts [71]. A staggering percentage of
people suffer from cataracts, the major cause of blindness in
the world. BlueMountains Eye study found that long-term use
of vitamin B2, B12, and folate supplements was associated
with a reduced prevalence of either nuclear or cortical cata-
racts [72]. As has been noted in the research, FA in combina-
tion with other supplements seems to be protective against
some kinds of cataracts.
At the corneal level, it has been observed reversible
corneal epitheliopathy is caused by vitamin B12 and
folate deficiency in a vegan with a genetic mutation
for the C677T of the methylenetetrahydrofolate gene.
The patient had been complained of decreased vision,
photophobia, and monocular diplopia [55]. Chronic
conjunctivitis was also associated with FA deficiency
[73]. According to the authors, few weeks after starting
FA supplementation, patient’s eye symptoms had
disappeared.
FA deficiency in animal models
Nutritional animal models are essential to understand human
diseases. In fact, animal studies can play an important role in
public health nutrition including the prevention of several
physiological, biochemical, metabolic, and molecular
diseases.
There is a strong relationship between FA and formate.
Increased formate production has been confirmed in folate-
deficient rats [74, 75]. Previous studies have shown that
formate-induced retinal dysfunction due to retinal toxicity is
characterized by photoreceptor cell dysfunction and damage,
as well as retinal edema [74].
To determine the role folate intake has in lens development,
a study was recently carried out by Muccioli et al. [51] on
embryonic and adult lenses, using the Le-Cremice. This study
reveals that embryos with aberrant lens fiber organization pre-
sented smaller lenses. Adult eyes accompanied by cataracts
were also microphthalmic. These results are consistent with
studies by our research group in which we have observed that
maternal FA deficiency alters ocular biometry of mouse em-
bryos. The size of the whole eye and lens was always smaller
than that of control. The reduction in size was usually accom-
panied by changes in the circularity of the lens and the entire
eye, both becoming more circular [76].
Elsewhere, Folr1-deficient mice have been shown to have
abnormal embryonic development. The malformations in-
cluded ocular defects, such as unilateral or bilateral
anophthalmia and microphthalmia. The percentages of adult
and embryonic Folr1-deficient mice observed with ocular de-
fects were similar (14–24%) [77]. Another research team [78]
Fig. 1 Organization of the neural
retina. ONL, outer nuclear layer;
OPL, outer plexiform layer; INL,
inner nuclear layer; IPL, inner
plexiform layer; GCL, ganglion
cell layer; NFL, nerve fiber layer
1576 Graefes Arch Clin Exp Ophthalmol (2019) 257:1573–1580
also found that mice exposed to a FA-deficient diet exhibited
anophthalmia and microphthalmia. Likewise, in the same
study, severe eye abnormalities such as alterations in the reti-
na, corneal stroma, corneal endothelium, corneal epithelium,
lens, iris, ciliary body, anterior chamber, and vitreous body
have been noted. Moreover, eye defects have been produced
in rat fetuses as a result of maternal FA deficiency in various
stages of gestation. Ocular abnormalities included
anophthalmia, microphthalmia, reduction or absence of optic
nerve fiber, duplication of the optic cup, retinal folding, retinal
coloboma and eversion, rupture of the anterior lens capsule
and posterior lentiglobus, lens vacuolation, ectopia lentis, and
disorganization of the corneal layers [79]. Further, the impact
of folate deficiency in zebrafish was studied. It has been ob-
served that folate deficiency induced oxidative stress and im-
paired neural tube closure in embryos. As a result, many ab-
normalities of eye development occurred, such as smaller eyes
and loss of cellular layers and optic nerve [80].
Another alteration that could be linked to folate deficit is
autoimmune uveitis (AU). This is a T cell-mediated disease
caused by immune responses to retinal autoantigens. The eti-
ologic causes of this disease are unclear, but it is often asso-
ciated with certain rheumatic disorders, such as rheumatoid
arthritis and Behcet’s disease, which is characterized by recur-
rent intraocular inflammation, glaucoma, cataracts, and vision
loss [81–83]. Macrophages play a crucial role in AU. Acute
inflammation is usually initiated by these cells [84, 85]. Some
studies have shown the presence of macrophages in different
stages during AU evolution. The macrophages induce an au-
toimmune response that provokes cell death and the elimina-
tion of T cells in the retina [86]. In other words, macrophages
are effectors of innate immunity and inductors of acquired
immunity in eye inflammation processes like AU [87].
Moreover, high numbers of macrophages are known to be
present during inflammation processes [88]. As stated above,
FR-β is considered as a biomarker for activated macrophages
associated with the pathogenesis and progression of autoim-
mune and inflammatory disorders [34, 89]. Recent studies
have demonstrated that FR-β is expressed and is functional
in synovial macrophages in rheumatoid arthritis in humans
[90] and in the retinas of rats with experimental autoimmune
uveitis (EAU) [52]. A study by Lu et al. on rats with autoim-
mune uveitis confirmed increased FR-β levels in retinal cells.
Rat models of EAU were treated with doses of EC0746, an
anti-inflammatory drug conjugate consisting of modified FA.
Overall, EC0746 therapy achieved a ~ 99% reduction in EAU
disease activity. These results suggest that the anti-
inflammatory activity of EC0746 was specific for folate
receptor-expressing cells.
As can be seen, folate deficiency has deleterious conse-
quences for the eye, particularly the retina.
In the final analysis, it seems that many of ocular alterations
are because FA deficiency alters extracellular matrix protein
expression, like collagen IV and laminin-1. Our research
group has shown that the spatial expression of both molecules
was altered in the lens [91]. Therefore, this alteration was also
linked to alteration of lens and retina tissue textures [92].
Conclusion
The aim of the present review is to investigate whether there is
a direct association between FA deficiency and eye diseases.
Several studies have demonstrated that FA plays an important
role in the prevention of some congenital anomalies such as
neural tube defects and spina bifida [93], congenital heart
defects [94], and orofacial clefts [95], as well as in chronic
diseases in adults, such as cancer [96], depression [97], and
age-related hearing loss [98].
Localization of folate receptor protein isoforms, reduced
folate transporter, and proton-coupled folate transporter is nor-
mally present in several eye tissues. There is therefore no
doubt that our eyes need FA and that this is essential for eyes
at all ages. This justifies the importance of taking this vitamin
in order to have healthy eyes and good vision. Regrettably,
there are presently only a few studies, to our knowledge, on
the role of FA in the prevention and treatment of eye disorders.
Future experiments to understand the relationship between FA
deficiency, alterations in the transport of folate, and eye dis-
ease are deemed necessary to reach a broader conclusion.
Funding information This review has been possible thanks to fundingof
the Complutense University of Madrid and the Bank of Santander (refer-
ence number CT27/16 - CT28/16). Likewise, it was supported by grants
from the Spanish Ministry of Economy and competitiveness (TEC2013-
40442).
Compliance with ethical standards
Conflict of interest The author declares that she has no conflict of
interest.
Ethical approval This article does not contain any studies with human
participants or animals performed by the author.
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https://doi.org/10.1007/s00417-018-4176-5
	Folic acid deficiency and vision: a review
	Abstract
	Introduction
	A brief description of human eye development
	Folate transport proteins and their localization in ocular structure
	Folic acid deficiency and ocular disease
	FA deficiency in patients
	FA deficiency in animal models
	Conclusion
	References