in cases of central perimacular retinopathy, is diagnosticforAlportsyndrome,andissignificantly associated with early-onset renal failure.

Ciliopathies

The ciliopathies are systemic disorders that result in a wide range of abnormalities. This is due to the fact that cilia are common organelles present on nearly every cell in the human body, and their dysfunction can thus lead to pleiotropic disorders [55]. There are three basic categories of cilia: motile, primary, and nodal. The most well known are the motile cilia, which beat in an orchestrated wavelike fashion on the surface of epithelial cells and are involved in fluid and cell movement. Primary cilia are solitary organelles that project from the surface of cells and lack the central pair of microtubules needed to generate motile force. These cilia are involved in renal and retinal disease. A third class of cilia, nodal cilia, plays an essential role in embryology and the establishment of the left-right body axis.

Retinal and renal dysfunction is observed across a range of ciliopathies. This is due to defects in photoreceptor and renal cilia, respectively. In the retina, the primary, or sensory, cilium of photoreceptors mediates polarized trafficking of proteins for efficient phototransduction. Genetic defects in these cilia lead to retinal dysfunction. For example, retinitis pigmentosa GTPase regulator (RPGR) is a cilial-centrosomal protein mutated in over 70% of X-linked retinitis pigmentosa cases [56].

The retinal ciliopathies include selected subtypes of retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, and Leber congenital amaurosis, as well as retinal degenerations associated with Bardet-Biedl syndrome, Senior-Loken syndrome, Usher syndrome, primary ciliary dyskinesia, Joubert syndrome, Laurence-Moon syndrome, McKusick-Kaufman syndrome, and Biemond syndrome. Mutations for these disorders have been found in retinitis pigmentosa-1 (RP1), retinitis pigmentosa GTPase regulator (RPGR), retinitis pigmentosa GTPase regulator interacting protein (RPGR-IP), as well as the

Usher, Bardet-Biedl, and nephronophthisis genes. Other systemic disorders associated with retinal degenerations that also involve ciliary abnormalities include the Alström, Jeune, Edwards-Sethi, Ellis-van Creveld, MeckelGruber, orofaciodigital type 9, and Gurrieri syndromes.

Understanding these conditions as ciliopathies may help the ophthalmologist recognize associations between seemingly unrelated diseases and have a high degree of suspicion that a systemic finding may be present. Several of these diseases, such as Bardet-Biedl, Alström, and Senior-Loken syndromes, affect both the retina and the kidneys and will be discussed further.

Bardet-Biedl, Alström, and Related

Syndromes

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathic genetic disorder characterized by six major features: retinal degeneration, renal dysfunction, central obesity, intellectual impairment, polydactyly, and hypogonadism [57]. However, the entire spectrum of abnormalities in BBS is only seen in a minority of patients. Intellectual impairment, polydactyly, and hypogonadism might be absent in female patients [58]. Nevertheless, retinal dystrophy is a consistent finding. The renal component of the disease significantly reduces patients’ life expectancy, and ESRD is usually noted as the primary cause of death [59], although renal transplantation has a reasonably good outcome in BBS [60]. Histopathologically, the kidney abnormalities resemble those seen in Senior-Loken syndrome, another ciliopathic retinal-renal disorder discussed later in this chapter.

Bardet-Biedl syndrome can show a wide spectrum of retinal disease expression (Table 27.4) [61]. The retinal degeneration in BBS can be demonstrated via electroretinography (ERG) before morphological changes take place. There is progressive photoreceptor damage, leading to macular and peripheral retinal atrophy, pigment migration, vascular attenuation, and optic nerve head atrophy. The photoreceptor damage is

Table 27.4 Spectrum of retinal disease expression in Bardet-Biedl syndrome (Adapted from [63])

fields than those with BBS1 [66]. However, it seems that all patients with mutations in BBS1 have some degree of maculopathy [66]. Optical coherence topography shows a disrupted inner and outer photoreceptor segment layer and a thinned RPE [66].

Senior-Loken Syndrome and Related Syndromes with Nephronophthisis

morphologically similar to the degeneration observed in patients with Alström syndrome [62] and Leber congenital amaurosis [63]. It has been suggested that photoreceptor cell death might be due to an underlying defect in the function of the connecting cilium, a structure that links the inner segments to the outer segments of photoreceptors [64]. This leads to abnormal dark adaptation within the first decade of life. However, visual loss is limited during this first decade and generally manifests clinically in the second decade.

Morphologically, the posterior pole is characterized by bull’s eye maculopathy. Peripherally, morphological signs of retinitis pigmentosa develop, with bony spicules appearing in the midperiphery. The pathology consists of primary degeneration of photoreceptors and secondary involvement of the other retinal layers, including the RPE, has been suggested. Overlapping oculorenal syndromes include Biedmond II syndrome, which is identical to BBS syndrome but also has an associated iris coloboma, and Alström syndrome, which is associated with diabetes mellitus and deafness but lacks polydactyly. The ocular abnormalities in Alström syndrome manifest earlier in life than they do in BBS. In Alström syndrome, retinitis pigmentosa with severe visual disability has been reported within the first year of life [65].

The retinal dystrophy is progressive and shows variable severity. To date, 12 BBS genes have been identified, with BBS1 and BBS10 being the most common [64]. All patients with the BBS1 mutation show some degree of maculopathy, whereas those patients carrying BBS10 mutations had more severely reduced VA and smaller visual

Nephronophthisis is an autosomal recessive, chronic tubulointerstitial nephropathy (−phthisis; wasting away), and it is the most common genetic cause of ESRD in children and adolescents [67]. It can occur in combination with tapetoretinal degeneration, in which case it is referred to as Senior-Loken syndrome (SLS), or in combination with other systemic abnormalities with or without retinal degeneration. SLS accounts for approximately 15% of nephronophthisis cases when a retinopathy and family history suggestive of autosomal recessive inheritance are seen [68]. When nephronophthisis is associated with tapetoretinal degeneration, cone-shaped epiphyses, and cerebellar ataxia, it is referred to as Mainzer-Saldino syndrome. The Boichis syndrome is the association of nephronophthisis with liver fibrosis, and it may occur in combination with deafness, cerebellar ataxia, and tapetoretinal degeneration [69]. Nephronophthisis and retinal degeneration have also been reported in association with asphyxiating thoracic dystrophy (Jeune syndrome) and with mitochondrial cytopathy and features of Kearns-Sayre syndrome.

Senior-Loken syndrome (SLS) is a rare autosomal recessive disorder characterized by the combination of familial juvenile nephronophthisis and tapetoretinal degeneration similar to Leber amaurosis, with or without mental retardation. First described in 1961 by Senior et al. [70] and Loken et al. [71] as an association of tapetoretinal degeneration with familial juvenile nephronophthisis, this syndrome is occasionally referred to as renal-retinal syndrome, juvenile nephronophthisis with Leber amaurosis, and renal dysplasia and retinal aplasia [72]. SLS is a