Ocular Pathology of Fukuyama Congenital Muscular Dystrophy

Tomoko Yamamoto, Yoichiro Kato and Noriyuki Shibata

### Abstract

Fukuyama congenital muscular dystrophy (FCMD) is one of the congenital muscular dystrophies, showing central nervous system (CNS) and ocular lesions, in addition to muscular dystrophy. It is included in α-dystroglycanopathy, an entity of muscular dystrophies caused by reduced glycosylation of α-dystroglycan (α-DG). Studies of ocular lesions are not so many, compared with those of the muscle and CNS. Clinical ocular manifestations are myopia, strabismus, retinal detachment, and so on. Since the retina has a structure partly resembling the cerebral cortex, pathological findings similar to those found in the brain have been reported. The major observation considered to be involved in the pathogenesis of retinal lesions is abnormalities in the internal limiting membrane formed by Müller cells, which is corresponding to the glia limitans formed by astrocytes in the brain. Fukutin, responsible for FCMD, and α-DG are expressed in Müller cells. Moreover, fukutin may be involved in synaptic functions of retinal neurons through the glycosylation of α-DG. In this chapter, ocular lesions of fetal and child FCMD patients are presented, especially focusing on pathological findings of the retina, and functions of fukutin are discussed.

Keywords: eye, pathology, Fukuyama, muscular dystrophy, fukutin

### 1. Introduction

Fukuyama congenital muscular dystrophy (FCMD), described by Fukuyama et al., is an autosomal recessive disease, exclusively found in Japan [1, 2]. In addition to the muscular dystrophy, central nervous system (CNS) and eye anomalies are accompanied. Although there are mild to severe cases, patients are generally noticed as floppy infant, exhibit progressive muscular dystrophy and mental retardation, and die before 30 years [2]. The responsible gene is fukutin on chromosome 9q31 [3]. Among congenital muscular dystrophies, Walker Warburg syndrome (WWS) and muscle-eye-brain disease (MEB) show characteristics similar to FCMD [4, 5], although patients of FCMD show milder symptoms compared to those of WWS and MEB, in general [6]. Since responsible genes for WWS, MEB, and FCMD are implicated in the glycosylation of α-dystroglycan (α-DG), they are included in the entity of α-dystroglycanopathy [6].

At the sarcolemma of skeletal muscle, there is a complex composed of several proteins, including dystroglycans, sarcoglycans, and dystrophin. It is called the dystrophin-glycoprotein complex (DGC) that links extracellular matrix and intracellular proteins. The DGC is also observed in the CNS and in 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].

the basement membrane fragile and this gives rise to partial defects in the glia limitans. Amounts of overmigrated neuronal tissues are various, depending on the

retinal dysplasia and introducing resent studies on pathogenesis.

2. Normal development and structure of the eye

Ocular Pathology of Fukuyama Congenital Muscular Dystrophy

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

2.1 Normal development of the eye

periocular mesenchyme by 15 weeks.

2.2 Normal structure of the eye

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Compared with the muscular and CNS lesions, studies about the ocular anomaly are rather scarce, but intriguing observations have been reported. Among the components of the eye, the retina has some characteristics common to the cerebral cortex. In this chapter, ocular lesions of FCMD are described, mainly focusing on

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

The retina is differentiated from the optic cap. The inner layer of the optic cap

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

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].

size of defects [20, 23, 24].

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

#### Figure 1.

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 matrix,T: thalamus.

the basement membrane fragile and this gives rise to partial defects in the glia limitans. Amounts of overmigrated neuronal tissues are various, depending on the size of defects [20, 23, 24].

Compared with the muscular and CNS lesions, studies about the ocular anomaly are rather scarce, but intriguing observations have been reported. Among the components of the eye, the retina has some characteristics common to the cerebral cortex. In this chapter, ocular lesions of FCMD are described, mainly focusing on retinal dysplasia and introducing resent studies on pathogenesis.
