3.3 Pathological consideration on retinal lesions of FCMD

In the CNS, fukutin and other related proteins are expressed in both glial cells and neurons [7, 34, 35]. Similarly, in the eye, fukutin is expressed in retinal neurons in addition to Müller cells [31, 36] (Figure 5).

Just above the inner limiting membrane formed by Müller cells abutted the basement membrane containing components of the DGC [37–39]. Like the CNS, abnormal basement membrane in the retinal surface may be involved in the pathogenesis of retinal dysplasia [31]. Focal fusion of the retina also may be caused by abnormal basement membrane. The glycosylation of α-DG is decreased in the inner limiting membrane of FCMD cases. Abnormalities of the basement membrane [40], decreased glycosylation of α-DG at the inner limiting membrane, and reactive gliosis [41] also have been reported in model mice of MEB. The study using αdystroglycanopathy model mice and dystroglycan mutant mice suggest that DG is required for the maturation and maintenance of the inner limiting membrane, rather than its initial formation [42]. Retinal neurons can migrate properly under well-formed inner limiting membrane [42]. Although fukutin-null mice are lethal during pregnancy [43], the basic structure of retina and brain is relatively well kept in the early stage of the gestation of FCMD patients. Fukutin is considered to be essential for the embryogenesis. Severity of anomalies depends on a degree of functional loss of fukutin. On the brain of FCMD, lesions appear to be obvious after the second trimester. Strength of the surface structure may not catch up with the rapid increase of the volume of eye and brain. One of the interesting things is that the glycosylation of α-DG around the capillary is maintained. In POMGnT1 knockout mice, the basement membrane of pigmented epithelium looks intact [40].

Müller cells have various roles to maintain retinal functions. One of the roles is to eliminate an excess of glutamate, a major transmitter in the retina, from the synaptic space. Glutamate is transported into Müller cells by glutamate transporter-1 (GLT-1) and metabolized to ornithine by ornithine aminotransferase (OAT) or to glutamine by glutamine synthase (GS). In FCMD patients, function of Müller cells seems to be decreased, because the expression of GLT-1, OAT, and GS is decreased [31].

In addition to the inner limiting membrane, the dystrophin-glycoprotein complex exists at presynaptic terminals of photoreceptor cells [41, 44]. As a ligand of α-DG, pikachurin is important for synaptic function between photoreceptor cells and bipolar cells [44]. In DG-knockout mice, pikachurin is markedly lost in both rod and cone photoreceptors with the loss of DG in these cells [44]. With the absence of DG, the retina becomes thin showing a decrease of photoreceptor cells, horizontal cells, and retinal ganglion cells in mice [42]. Decrease of ERG b-waves is observed in pikachurin-deficient mice and in dystroglycan-deficient mice [39]. Similar retinal lesions and abnormal ERGs are found in fukutin- [45], POMGnT1- [41], and Pomt1- [46] deficient mice, and Largemyd and Largevls mice [47]. Hypoglycosylation of α-DG by hypofunction of fukutin and other proteins is considered to affect the function of retinal neurons as well as that of Müller cells.

Figure 4.

67

plexiform layer, ONL: outer nuclear layer.

Retinal findings in FCMD children. The retina is detached from the pigmented layer and abnormally folded (A, B), with focal surface fusion (arrows). In a severe case, retinal structure is abnormal with discontinuous PAM-positive structures, probably in the layer of photoreceptor cells. Normally, there is no such structure in this layer (C, D). Rosette structures are focally seen (E). The retina becomes thin with scarce retinal neurons (F). G and H show normal retina. The space indicated by the asterisk is an artifact during tissue preparation. Ch: choroid, Sc: sclera, GCL: ganglion cell layer, IPL: inner plexiform layer, INL: inner nuclear layer, OPL: outer

Ocular Pathology of Fukuyama Congenital Muscular Dystrophy

DOI: http://dx.doi.org/10.5772/intechopen.82775

Ocular Pathology of Fukuyama Congenital Muscular Dystrophy DOI: http://dx.doi.org/10.5772/intechopen.82775

hyperplastic primary vitreous body and a persistent hyaloid artery are also reported [31]. In severe cases, the layer of retina is markedly distorted with or without rosette formation. The outer and inner nuclear layers became thin in part. The layer of photoreceptor is also deranged with abnormal appearances of periodic acidmethenamine-silver (PAM)-positive structure (Figure 4). Reactive gliosis can be seen [31]. Severity of retinal dysplasia appears to be parallel to that of the CNS

In the CNS, fukutin and other related proteins are expressed in both glial cells and neurons [7, 34, 35]. Similarly, in the eye, fukutin is expressed in retinal neurons

Just above the inner limiting membrane formed by Müller cells abutted the basement membrane containing components of the DGC [37–39]. Like the CNS, abnormal basement membrane in the retinal surface may be involved in the pathogenesis of retinal dysplasia [31]. Focal fusion of the retina also may be caused by abnormal basement membrane. The glycosylation of α-DG is decreased in the inner limiting membrane of FCMD cases. Abnormalities of the basement membrane [40], decreased glycosylation of α-DG at the inner limiting membrane, and reactive gliosis [41] also have been reported in model mice of MEB. The study using αdystroglycanopathy model mice and dystroglycan mutant mice suggest that DG is required for the maturation and maintenance of the inner limiting membrane, rather than its initial formation [42]. Retinal neurons can migrate properly under well-formed inner limiting membrane [42]. Although fukutin-null mice are lethal during pregnancy [43], the basic structure of retina and brain is relatively well kept in the early stage of the gestation of FCMD patients. Fukutin is considered to be essential for the embryogenesis. Severity of anomalies depends on a degree of functional loss of fukutin. On the brain of FCMD, lesions appear to be obvious after the second trimester. Strength of the surface structure may not catch up with the rapid increase of the volume of eye and brain. One of the interesting things is that the glycosylation of α-DG around the capillary is maintained. In POMGnT1 knockout mice, the basement membrane of pigmented epithelium looks intact [40]. Müller cells have various roles to maintain retinal functions. One of the roles is to eliminate an excess of glutamate, a major transmitter in the retina, from the synaptic space. Glutamate is transported into Müller cells by glutamate transporter-1 (GLT-1) and metabolized to ornithine by ornithine aminotransferase (OAT) or to glutamine by glutamine synthase (GS). In FCMD patients, function of Müller cells seems to be decreased, because the expression of GLT-1, OAT, and GS is

In addition to the inner limiting membrane, the dystrophin-glycoprotein complex exists at presynaptic terminals of photoreceptor cells [41, 44]. As a ligand of α-DG, pikachurin is important for synaptic function between photoreceptor cells and bipolar cells [44]. In DG-knockout mice, pikachurin is markedly lost in both rod and cone photoreceptors with the loss of DG in these cells [44]. With the absence of DG, the retina becomes thin showing a decrease of photoreceptor cells, horizontal cells, and retinal ganglion cells in mice [42]. Decrease of ERG b-waves is observed in pikachurin-deficient mice and in dystroglycan-deficient mice [39]. Similar retinal lesions and abnormal ERGs are found in fukutin- [45], POMGnT1- [41], and Pomt1- [46] deficient mice, and Largemyd and Largevls mice [47]. Hypoglycosylation of α-DG by hypofunction of fukutin and other proteins is considered to affect the

function of retinal neurons as well as that of Müller cells.

3.3 Pathological consideration on retinal lesions of FCMD

in addition to Müller cells [31, 36] (Figure 5).

lesion [31].

Muscular Dystrophies

decreased [31].

66

#### Figure 4.

Retinal findings in FCMD children. The retina is detached from the pigmented layer and abnormally folded (A, B), with focal surface fusion (arrows). In a severe case, retinal structure is abnormal with discontinuous PAM-positive structures, probably in the layer of photoreceptor cells. Normally, there is no such structure in this layer (C, D). Rosette structures are focally seen (E). The retina becomes thin with scarce retinal neurons (F). G and H show normal retina. The space indicated by the asterisk is an artifact during tissue preparation. Ch: choroid, Sc: sclera, GCL: ganglion cell layer, IPL: inner plexiform layer, INL: inner nuclear layer, OPL: outer plexiform layer, ONL: outer nuclear layer.

Conflict of interest

Author details

Tokyo, Japan

69

Shinjuku-ku, Tokyo, Japan

provided the original work is properly cited.

The authors declared that they have no conflict of interest.

Ocular Pathology of Fukuyama Congenital Muscular Dystrophy

DOI: http://dx.doi.org/10.5772/intechopen.82775

Tomoko Yamamoto1,2\*, Yoichiro Kato2 and Noriyuki Shibata1,2

\*Address all correspondence to: yamamoto.tomoko@twmu.ac.jp

1 Department of Surgical Pathology, Tokyo Women's Medical University Hospital,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Pathology, Tokyo Women's Medical University, Shinjuku-ku,

#### Figure 5.

Expression of fukutin in normal human retina. Fukutin is expressed in both retinal neurons and Müller cells (A–C). On fluorescent immunohistochemistry (A), fukutin is visualized in red (DAPI: blue). On Photoshopaided double immunohistochemistry, green color indicates the elements positive for both fukutin and GFAP. IPL: inner plexiform layer, INL: inner nuclear layer, OPL: outer plexiform layer, ONL: outer nuclear layer.

Immunoreaction against antifukutin antibody is found in all the retinal layers, with stronger intensity in the inner segments of photoreceptors and in the outer plexiform layer [36]. In our immunostaining on formalin-fixed, paraffin-embedded human retina, all the layers are stained, but more intense in the outer and inner nuclear layer (Figure 5). This may due to the difference of tissue preparation like fixation. As for subcellular localization of fukutin, in retinal cells, it is mainly localized in the endoplasmic reticulum rather than the Golgi apparatus and in the nucleus in vivo [36]. Similar localization is observed in carcinoma cell lines [48]. These observations are contradict to the general consideration that fukutin is localized in the Golgi apparatus on cultured cells transfected with fukutin [3]. Further examinations are needed to explain the difference and clarify the localization of fukutin in vivo. If fukutin is truly localized in the endoplasmic reticulum and nucleus, this might suggest further unknown functions of fukutin, regardless of the relation to the glycosylation of α-DG.

### 4. Conclusions

Among severe forms of α-dystroglycanopathy like WWS, MEB, and FCMD, apparent CNS and ocular lesions are accompanied. Pathology of ocular lesions shares some characteristics common with that of CNS lesions. In this chapter, representative pathological findings of the eye of FCMD are presented, mainly focusing on the retinal dysplasia, and its pathogenesis is discussed with the review of literatures.

#### Acknowledgements

The authors wish to thank Ms. Noriko Sakayori, Mr. Fumiaki Muramatsu, Mr. Hideyuki Takeiri, Mr. Shuichi Iwasaki, and Mr. Mizuho Karita for their excellent technical assistance.

Ocular Pathology of Fukuyama Congenital Muscular Dystrophy DOI: http://dx.doi.org/10.5772/intechopen.82775
