2. Normal development and structure of the eye

### 2.1 Normal development of the eye

The glycosylated area of α-DG existed outside the cell membrane works as a receptor for extracellular matrix proteins like laminin [6–8]. Thus, the glycosylation of α-DG is indispensable for formation of the basement membrane. To accomplish a fully glycosylated α-DG, several proteins, such as protein-O-mannosyltransferase 1/2 (POMT1/2) [9–11], O-linked mannose 1,2-N-acetylglucosaminyltransferase (POMGnT1) [12], fukutin [13], fukutin-related protein (FKRP) [14], and LARGE [15], are required. The recent study proves that fukutin transfers ribitol 5-phosphate to sugar chains of α-DG, which is necessary to make a functional α-DG [13]. Muscular dystrophies showing reduced glycosylation of α-DG due to malfunction of above proteins that add sugars on the glycosylation domain of α-DG are categorized to α-dystroglycanopathy, which include severe diseases like WWS, MEB, and FCMD to rather milder diseases like congenital muscular dystrophy 1C (MDC1C) [16], MDC1D [17], limb-girdle muscular dystrophy 2I (LGMD 2I) [16] LGMD2K, and LGMD2M [18]. In severe ones, CNS and eye anomalies are obvious. The CNS anomaly is represented by cortical dysplasia, generally called cobblestone lissencephaly [6, 7]. In FCMD, the cerebrum and cerebellum generally show an appearance of polymicrogyri [19–21]. In the surface of CNS, astrocytic endfeet form the glia limitans covered with the basement membrane, and both fukutin and α-DG are expressed in astrocytes [7, 22]. In the fetal FCMD brain, irregular disruptions of the glia limitans are observed. Neuronal tissues overmigrate from defects of glia limitans (Figure 1), which is considered to be the main cause of cobblestone lissencephaly [7, 8]. Hypoglycosylation of α-DG by malfunction of fukutin makes

Cerebral lesions of a FCMD fetus. The cerebral hemisphere almost retains fundamental structure (A). The glia limitans of the cerebral surface is irregularly disrupted, and neuronal tissues overmigrate through the disruptions (B, C; arrows). (B) Periodic acid-methenamine-silver (PAM) staining. (C) Photoshop-aided double immunostaining [25] of nestin (green) and synaptophysin (brown). BG: basal ganglia, GM: germinal

Figure 1.

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matrix,T: thalamus.

Muscular Dystrophies

Many genes are involved in the formation of ocular structure [26]. Morphologically, the initial eye structure becomes observable after 3 weeks of the gestation, as a pair of optic sulci at the rostral neural plate. By 4 weeks, the optic sulcus grows to form the optic vesicle, the proximal part of which develops to be the optic stalk, the future optic nerve, and the rest of which to be the optic cap. The distal part of the optic vesicle is closely adjacent to the surface ectoderm that develops to the lens after forming the lens vesicle by invagination. The lens vesicle is separated from the surface ectoderm at 6 and half weeks. The corneal epithelium begins to be formed from the surface ectoderm by 7 weeks. The choroid and the sclera develop from the periocular mesenchyme by 15 weeks.

The retina is differentiated from the optic cap. The inner layer of the optic cap becomes the neural retina, and the outer layer becomes the retinal pigmented epithelium. After retinal neurons are born, they move to their proper place, mimicking the development of CNS. However, the retina has its own mode for lamination [27]. In the retina, retinal ganglion cells and cone photoreceptors differentiate earlier, and then rod photoreceptors, bipolar cells, and Müller cells [26–28].

#### 2.2 Normal structure of the eye

The eyeball can be divided into the anterior and posterior segments. The anterior segment includes the cornea, anterior and posterior chambers, iris, and lens. The posterior segment contains the vitreous, retina, choroid, sclera, and optic nerve (Figure 2).

Histologically, the normal retina consists of the inner and outer segments of photoreceptors, outer nuclear layer, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, and nerve fiber layer (Figure 2). Outer segments of the photoreceptor are loosely connected to retinal pigmented epithelia. Microvilli of the pigmented epithelium surround the outer segments of photoreceptors [29]. The outer nuclear layer contains nuclei of the photoreceptors, the rod and cone. Rods are extremely sensitive to light, while cones are involved in the color vision. In the outer plexiform layer, photoreceptors form synapses between bipolar cells: roughly, rods to rod bipolar cells and cones to cone bipolar cells. Rod bipolar cells depolarize (ON) to the increase of light intensity. On the other hand, cone bipolar cells either ON or hyperpolarize (OFF) [28]. The inner nuclear layer is mainly formed by bipolar cells. Cell bodies of amacrine cells, horizontal cells, and Müller cells are also contained. In the inner plexiform layer, synapses are formed between retinal ganglion cells and bipolar cells or amacrine cells. Synapses with ONbipolar cells are seen in the inner lamina of the inner plexiform layer and those with OFF-bipolar cells in the outer lamina [28]. In the ganglion cell layer, single to several layers of retinal ganglion cells are observed. The nerve fiber layer consisted

atrophy of the optic nerve, and retinal detachment are also known. Severe cases may show microphthalmia [31]. Electroretinogram (ERG) of FCMD patients may be normal, but abnormal findings may be seen in both dark-adapted and lightadapted ERGs [32]. Patients of WWS and MEB, severe forms of α-dystroglycanopathy, also exhibit abnormalities in anterior and posterior components. In

microphthalmia, retinal detachment, retinal dysplasia, and optic atrophy [4]. Glaucoma and buphthalmos also may be observed. Clinical ocular findings of MEB reported are myopia, nystagmus, optic atrophy, and retinal degeneration [33]. ERG is abnormal as well. Like the CNS, ocular anomalies of FCMD are less severe than

Although histological examinations of the eye of fetal FCMD cases are not so many, findings similar to those of the cerebrum can be found [31]. The inner limiting membrane is irregularly disrupted and ganglion cells exist beyond the inner limiting membrane, while there are areas exhibiting no apparent light microscopical abnormalities (Figure 3). Like child cases, some fetal cases may show local folding

In child FCMD cases, detachment, local folding, and fusion of the retina are observed (Figure 4). The inner limiting membrane is discontinuous. A persistent

Retinal findings in FCMD fetus. The internal limiting membrane, clearly depicted by PAM staining, is discontinuous in some part (A, B; arrows), while there are areas showing normal retinal appearance with continuous internal

limiting membrane (C, D). Ectopic ganglion cells are observed beyond the inner limiting membrane.

WWS, varieties of lesions are described, such as cataract, microcornea,

Ocular Pathology of Fukuyama Congenital Muscular Dystrophy

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

those of WWS and MEB [30, 31].

3.2 Histological findings

and fusion of the retina [31].

Figure 3.

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Figure 2. (A) Schema of normal eye structure and (B) structure of normal retina.

of nerve fibers of retinal ganglion cells is situated beneath the inner limiting membrane that is formed at the inner surface of the retina by Müller cells. The external limiting membrane is formed by zonula adherens between Müller cells and inner segments of photoreceptor [29]. The basement membrane is abutted above the inner limiting membrane and beneath the basal surface of pigmented epithelium, attaching to the Bruch's membrane [29]. The basement membrane is also formed around capillaries.
