Fig. 27.7 Senior-Loken syndrome: Both the color photograph (a) and the early-phase fluorescein angiograph show an atrophic “bull’s eye” macular lesion (white arrows) and

peripheral retinitis pigmentosa, as evidenced by retinal atrophy with bone spicules (black arrows). This patient had very poor vision and end-stage renal disease

ciliopathy. In the retina, the outer segments of photoreceptor cells, which are in fact specialized sensory cilia, are affected. In the kidney, the primary apical cilia are affected. SLS is caused by a genetic defect of the nephronophthisis (NPHP) gene.

The retinopathy in SLS is variable and may be a form of severe infantile onset retinal dystrophy [73, 74], as a Leber congenital amaurosis type of abnormality [75] or as what appears as a typical retinitis pigmentosa [76]. The retinal degeneration tends to be severe, with poor visual acuities on the order of 20/200–20/400. Fundus abnormalities such as peripheral bone spicule formation, arteriolar narrowing, and optic disk pallor often appear later in the disease process (Fig. 27.7). Associated ocular findings include nystagmus, poor pupillary reflexes, retinal mottling, and high myopia. The ERG is often extinguished early in the disease. Visual field testing usually shows severe annular constriction of the visual fields [77].

A recent report of retinal imaging of a patient with SLS and poor vision focus emphasized the photoreceptors’ cilia appearance in the macula [78]. Fundus autofluorescence showed diffuse spots of decreased autofluorescence in the midperiphery and a perifoveal ring of increased

autofluorescence, suggesting a bull’s eye maculopathy. The inner-outer photoreceptor segment junction in the central macula, corresponding to the area inside of the ring of increased autofluorescence, was barely detectable on highresolution optical coherence tomography. This syndrome highlights the need for all children with a retinal dystrophy to have assessments of both their renal function and hearing.

Other Rare Metabolic Diseases

Congenital Disorders of Glycosylation (CDG)

The congenital disorders of glycosylation (CDG), previously known as the carbohydrate-deficient glycoprotein syndromes, are a group of rare inherited multisystem disorders resulting from genetic defects in protein glycosylation. These patients present in infancy. Although several genotypes exist, of which CDG-Ia has been most frequently described, common features of all CDG subtypes include moderate to severe neurological impairment, variable dysmorphic features, and variable involvement of other organs. Neurological disturbances frequently dominate the clinical picture and are characterized by psychomotor retardation,

hypotony, and ataxia. Patients may thus be very difficult to examine ophthalmologically.

Besides the central nervous system, the liver, kidney, pericardium, subcutis, kidney, and eyes can be involved. Ophthalmic findings involving both the anterior and posterior segment of the eye are frequent in CDG syndrome. Reported anomalies have included delayed visual maturation, strabismus, saccadic eye pursuits, retinal degeneration, and electrophysiological abnormalities [79–85]. In a more recent study, a majority (78%) of the patients with CDG-Ia was myopic, and a small minority was hypermetropic [86]. This study found the myopia to be progressive, at the rate of 0.8 diopters per year. Congenital esotropia and delayed visual maturation were consistent findings. Although some children might develop good visual acuity, the majority has low vision or is legally blind. Pallor of the optic disk is noted in about 20%, and electroretinography shows reduced rod responses, while cone responses are only slightly reduced. In the ocular fundus, attenuated retinal vessels may be observed in approximately half of the patients, indicative in this case of tapetoretinal degeneration.

It is recommended that patients be seen annually by an ophthalmologist, refracted regularly, and have glasses prescribed if myopia develops. Retinal function should also be examined regularly in order to document progression of the tapetoretinal degeneration [87].

Cystinosis

Cystinosis is a rare autosomal recessive disorder of lysosomal cystine transport characterized by intracellular accumulation of cystine, the disulfide of the amino acid cysteine [88, 89]. The accumulation is caused by a mutation of the CTNS gene, leading to defective or absent cystinosin [90], the membrane protein responsible for transporting cystine out of the cellular lysosome [91]. Crystal formation and organ damage ensue. In patients with cystinosis, different CTNS mutations produce different phenotypes. Although all nucleated cells in the body of affected patients carry the genetic defect, the kidney and the eye are particularly

vulnerable to this pathology and are the first to manifest symptoms. Other organs that can be affected are the pancreas, thyroid, brain, and muscle. The subsequent late systemic complications include short stature, diabetes mellitus, hypothyroidism, cerebral calcifications, dysphagia, and distal myopathy [92, 93].

Based on the patient’s age at onset, as well as the severity of the symptoms, several phenotypes have been described. Classification is based on the presence of kidney dysfunction (nephropathic cystinosis) or lack thereof (nonnephropathic cystinosis). Nephropathic cystinosis can be further divided into infantile (classic) and intermediate (juvenile-onset or adolescent). Nonnephropathic cystinosis, previously known as benign or adulttype cystinosis, is now referred to as ocular cystinosis, although nephropathic cystinosis is also characterized by ocular manifestations.

Infantile nephropathic cystinosis is both the most common and the most severe phenotype of cystinosis. These young patients present with growth retardation and Fanconi syndrome, a disorder of renal tubular function, during the first year of life. Untreated cases progress to end-stage renal disease (ESRD) later in the first decade of life [89, 94].

Corneal crystal deposits are so prominent and typical that early diagnosis can frequently be made before the manifestation of nephropathy [95]. Diagnosis is confirmed via conjunctival, bone marrow, or kidney biopsy, or via leukocyte cystine assay, in which detection of a 50–100-fold increase in the free cystine levels in polymorphonuclear leukocytes is observed. Leukocyte cystine assay is particularly useful in suspected children under 20 months who have a negative ocular examination. The diagnosis can also be made prenatally by means of a chorionic villi biopsy.

The ocular manifestations are highly characteristic, and their recognition can make a substantial contribution to the timely diagnosis of the disease. The most obvious sign is the formation of crystals in the cornea, visible on standard slit-lamp biomicroscopy. These crystals appear at approximately 1 year of age, and they progressively increase in density [96]. They are present throughout the corneal epithelium and the entire stroma.

Patients often present with photophobia. The differential diagnosis should include multiple myeloma, which can also present with corneal crystals and photophobia, albeit rarely [97]. However, in multiple myeloma, the crystals are limited to the epithelium and superficial stromal layers. Besides cystinosis and multiple myeloma, the differential diagnosis includes Bietti crystalline corneal and retinal dystrophy, Schnyder crystalline corneal dystrophy, Meesmann corneal dystrophy, Fabry disease, and reaction to certain drugs, such as amiodarone [97]. Measurement of the leukocyte cysteine, as well as the fact that the corneal crystals of cystinosis cause intense discomfort, can help distinguish between cystinosis and the other disorders.

Deposits in cystinosis are also present in other ocular structures, such as the conjunctiva, anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve [98]. However, these are less frequent. Whereas corneal crystals are present in approximately 90% of patients, fundus abnormalities, such as retinal, subretinal, retinal pigment epithelial, and/or choroidal changes, may only be visible in about 30–50% [99–101]. Retinal manifestations can vary. The most common fundus finding is peripheral RPE hypopigmentation with pigmentary stippling or mottling, present in approximately 60% and noted as early as 6 months [102]. Also possible is the combination of peripheral hypopigmentation and macular pigmentary changes, or a fundus resembling that seen in retinitis pigmentosa, with bone spicules and pigment clumps. Rare manifestations are severe chorioretinal atrophy, submacular neovascular membranes, and perimacular RPE atrophy [102]. Deep yellow crystals throughout the posterior pole as well as diffuse pigmentary changes without crystals have been described. Retinal crystals are present in approximately 10% [102]. The fundus appearance has been alternately described as “fine scintillating refractile bodies” scattered throughout the posterior pole in the RPE or choroid [103] and as simply yellow crystalline choroidal material [100]. Retinopathy without crystal deposition has also been described. In this case, it is confined to the RPE, with areas of hypertrophy, depigmentation, and atrophy

[104]. As patients grow older, the effects of the retinal degeneration become more apparent. These effects include nyctalopia, color vision problems, constricted visual fields, and decreased cone and rod function on ERG [105].

The cause of the retinal degeneration is unknown. Histopathological study has revealed diffuse RPE cell degeneration associated with the presence of intracellular crystals [106], which are located in the RPE and choroid [107–109]. Cellular apoptosis might also be responsible [89, 110].

Systemic treatment of the disease focuses on depletion of intracellular cystine using oral cysteamine, which improves the export of cystine from lysosomes and prevents progression of the disease [111]. However, early initiation of treatment is crucial, as cysteamine treatment may not reverse renal pathology [112]. Dialysis and/or renal transplantation is performed in case of ESRD, and chronic cystine depletion therapy is maintained post-transplantation.

Corneal deposits are not affected by oral cysteamine therapy, so cysteamine is administered topically (0.5% cysteamine eyedrops) [113]. This removes the corneal crystals and improves the associated photophobia and recurrent corneal erosions [114–116]. However, strict compliance with 6-hourly dosing is needed for proper cystine depletion [100]. Topical therapy has been shown to decrease retinal cystine infiltration [117]. The frequency of cystinotic retinopathy has been shown to correlate positively with time off cysteamine therapy and negatively with time on cysteamine therapy [118]. Oral cysteamine therapy should begin as early as possible and should not be stopped even after renal transplantation.

Fabry Disease

Fabry disease (FD), also known as angiokeratoma corporis diffusum or a-galactosidase deficiency, is an X-linked, hereditary, lysosomal storage disease caused by deficiency of the enzyme a-galac- tosidase A. This enzyme deficiency results in the systemic accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in nearly every body tissue. Clinically, the disease is characterized

by progressive renal impairment, chronic pain and acroparesthesia, gastrointestinal disturbances, cutaneous angiokeratomas (small bluish-black, nonblanching telangiectasias), cardiomyopathy, and stroke. Diagnosis is confirmed by detection of decreased levels of a-galactosidase A in the plasma or in PMNs. Without treatment, the disease is fatal. The possibility of life-saving treatment has heightened the importance of early diagnosis so that treatment can be initiated before organs become irreversibly damaged. Treatment currently consists of intravenous enzyme replacement therapy with recombinant a-galactosidase A.

The ocular manifestations frequently present early in the disease process and can be detected upon routine ophthalmic exam. They include cornea verticillata (whorl-like radial lines emanating from a single vortex and potentially covering the entire cornea), conjunctival vessel tortuosity and aneurysmal dilation, lens opacities (posterior lens cataract), and retinochoroidal vessel abnormalities. The fundus abnormalities include retinal vessel tortuosity, irregular venous dilations, vascular sheathing, vascular occlusions, and retinal and preretinal bleeding. Characteristically, there are also anterior snowflake cataracts and, in males and carrier females, posterior lens posterior spoke-like cataracts.

Retinal vascular tortuosity is the most common retinal finding in FD, found in 77% of males and 19% of females, with the earliest reported presentation at age 13 in girls and age 11 in boys [119]. The arterioles are most commonly involved, although the venous side of the retinal circulation is involved in advanced cases. Venules assume a corkscrew appearance, and venous aneurysmal dilatation occurs. Although the ovular lesions do not typically affect the vision, both arterial and venous occlusions have been described [120, 121]. Delayed flow on FA is common in both male and female patients [117]. Indeed, FD is in fact a vasculopathy, and the diagnosis should be considered when a young patient presents with a central retinal artery occlusion [120, 122, 123]. Rarer findings include optic atrophy [123], central retinal vein occlusion [121, 124], and ischemic optic neuropathy [125]. A large minority of FD patients (44% in one

study) have an enlarged blind spot on visual field testing (20° horizontally and 25° vertically), although neither dyschromatopsia nor an afferent papillary defect is present in FD [126].

Delays in diagnosis of Fabry disease are unfortunately common. Indeed, the average age at diagnosis is 29 [127, 128], and patients frequently see several specialists before the correct diagnosis is made. Ophthalmologists have the opportunity to make a timely diagnosis, before the disease is well advanced.

The Zellweger Syndrome Spectrum

and Other Peroxisomal Diseases

Defects in PEX genes impair peroxisome assembly and many metabolic pathways in the peroxisome, providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD). The Zellweger syndrome spectrum, which represents the major type of PBD, includes three phenotypes that were identified and described before the biochemical and molecular bases of these disorders had been fully determined. They include Zellweger syndrome, the most severe; neonatal adrenoleukodystrophy; and infantile Refsum disease, the least severe.

Previously referred to as cerebrohepatorenal syndrome, Zellweger syndrome is an autosomal recessive disease whose pathogenesis derives from the defective assembly of peroxisomes. It is considered the prototypical peroxisomal biogenesis disorder, and it is also the most lethal. In other peroxisomal disorders, such as X-linked adrenoleukodystrophy (described later; not to be confused with neonatal adrenoleukodystrophy) and primary hyperoxaluria type 1 (described earlier in this chapter), the metabolic abnormality is generally limited to a single peroxisomal enzyme. However, in Zellweger syndrome, as in the two other phenotypes included in the spectrum, all peroxisomes are defective.

The problem lies in the abnormal b-oxidation of several very-long-chain fatty acids. This leads to anomalous lipid metabolism and very low levels of docosahexaenoic acid (DHA), which is considered to be the most important polyunsaturated fatty