OA may be helpful. In addition, a visual evoked potential may be useful to detect the misrouting of ganglion cells of the temporal retina typically seen in these disorders. This abnormality can be detected early in life and may be helpful in making the diagnosis of OCA during the neonatal period [11].

Treatment includes the correction of refractive error when necessary and the use of low vision aids if needed. Patients should be referred to a dermatologist for proper skin care. Genetic counseling is helpful due to the hereditary nature of these disorders. Patients in whom Hermansky–Pudlak or Chediak–Higashi syndromes are possible should also be referred for appropriate consultation.

6.1.2  Gyrate Atrophy

Gyrate atrophy of the choroid and retina is a rare autosomal recessively inherited, progressive, metabolic chorioretinal dystrophy beginning in childhood. It is caused by a deficiency in the mitochondrial matrix enzyme ornithine aminotransferase (OATase), resulting in hyperornithinemia [12]. Aside from visual impairment, patients with gyrate atrophy are for the most part asymptomatic. Mild to moderate diffuse slowing on electroencephalography has been reported in fewer than one-third of affected patients [13]. However, seizures have not been documented with increased frequency, and the majority of patients have normal intelligence [13]. Liver biopsies in patients with gyrate atrophy have demonstrated nonspecific morphologic abnormalities of the mitochondria, with elongation, branching, and segmentation [14]. The functional significance of these mitochondrial abnormalities is not known. The major clinical problem in patients with gyrate atrophy is a slowly progressive loss of vision leading to blindness, usually by the fourth decade of life. Myopia or decreased night vision is the earliest symptom, usually noted before the end of the first decade of life. Constriction of the visual field is obvious by the second decade. By age 40, most patients show visual fields smaller than 10° [15]. Posterior subcapsular lens changes develop in late adolescence.

During late childhood, sharply demarcated, circular areas of chorioretinal degeneration in the midperiphery can be detected (Fig. 6.2). There may be increased pigmentation around the margins of these lesions. During the second decade, the lesions enlarge, coalesce, and

Fig. 6.2  Fundus in gryrate atrophy

extend toward the posterior pole of the retina. By the third decade, much of the retina is involved, although foveal lesions are rarely present until very late in the course of the disease. Histologic examination of an affected retina has shown focal areas of photoreceptor atrophy with adjacent retinal pigment epithelial hyperplasia. Electron microscopy has revealed mitochondrial abnormalities of the photoreceptors [16].

The electroretinogram (ERG) eventually diminishes in amplitude and is usually extinguished well before the entire retina is involved clinically. The electro-­ oculogram becomes severely diminished, parallel to the reduction in the ERG. The slow progression of the degenerative changes in gyrate atrophy and the difficulty in measuring small changes in ocular function objectively make evaluation of any therapy difficult. Two therapeutic approaches have been attempted in patients with gyrate atrophy: reducing the accumulation of ornithine and stimulation of residual OATase activity. Arginine is the precursor of ornithine. A chronic diet restricted in arginine has been shown to lower ornithine levels and slow the progression of the ocular disease [17]. Some patients respond to pharmacologic doses of pyridoxine (vitamin B6) to increase the level of pyridoxal phosphate, a cofactor of OATase. A different single nonsense mutation within the OATase gene leads to a difference in the affinity of the enzyme for pyridoxal phosphate, accounting for the positive response to pyridoxine in this subset of patients [18].

6.1.3  Cystinosis

Cystinosis is an autosomal recessively inherited disorder of amino acid metabolism characterized by the deposition of cystine crystals in various tissues such as the eye, bone marrow, lymph nodes, and internal organs. Cystinosis is

a lysosomal storage disorder that results from impaired transport of the disulfide amino acid cystine from cellular lysosomes. It differs from other lysosomal diseases because the main enzyme function of lysosomes, acid hydrolysis, does not play a role in cystine deposition.

Three clinical types of cystinosis have been described, all of which have ocular involvement. The infantile, or nephropathic, variety is the most severe form of cystinosis [19]. During early childhood, affected patients develop polyuria and polydipsia as a result of impaired renal tubular water reabsorption. This is followed by growth retardation, renal rickets, metabolic acidosis and progressive renal failure.

Children with nephropathic cystinosis usually develop severe photophobia within the first few years of life. Slitlamp examination discloses diffuse scintillating, tinsellike crystals of the cornea, conjunctiva, and iris [20]. In patients with longstanding disease, thinning and focal breaks in Bowman’s membrane may be present and contribute to the development of severe photophobia [21].

The essential fundus abnormality is a patchy depigmentation of the periphery and a finer “salt-and-pepper” disturbance at the posterior pole [22]. Crystal deposition may also be seen. Despite the extensive tissue infiltration of cystine crystals, there is no significant visual disturbance.

Cysteamine is a cystine-depleting agent used in the treatment of infantile nephropathic cystinosis. When given systemically, it has proven to be successful in retarding glomerular deterioration and enhancing growth, but it does not prevent the development of corneal crystal formation [23]. Topical cysteamine drops have been shown not only to provide primary prevention of corneal crystal deposition but may also reverse the corneal complications in older patients [24].

Adolescent cystinosis is a milder form of the disease, appearing in the first or second decade of life. This type of cystinosis may or may not include rickets, renal failure, photophobia, or retinopathy. All patients have shown the crystalline material in the cornea, conjunctiva, and reticuloendothelial system.

A benign adult form of cystinosis also occurs. The primary clinical distinction between the benign and the nephropathic variants is failure of the former patients to show either retinopathy or renal dysfunction. Although affected patients may have mild photophobia, they are frequently diagnosed by routine ophthalmologic ­examination when the typical corneal crystals are noted.

Fig. 6.3  Fundus findings in hyperoxaluria

6.1.3.1  Primary Hyperoxaluria

Primary hyperoxaluria (PH) is an autosomal recessive condition characterized by the overproduction and accumulation of oxalic acid. In the kidneys, the excess oxalate combines with calcium to form calcium oxalate, a main component of kidney stones. Deposition of calcium oxalate can eventually lead to renal failure.

Two types of PH exist. PH1 is caused by a deficiency of the liver-specific enzyme alanine-glyoxylate aminotransferase [25]. PH2 is secondary to a deficiency of cytosolic D-glycerate dehydrogenase/glyoxylate reductase [26]. PH1 causes widespread accumulation of oxalate crystals in the extra renal tissues including the eye, bone, and heart. PH2 is a less severe disease without signs of systemic oxalosis.

Although oxalate crystals are deposited throughout the eye, retinopathy is the dominant clinical finding. Initially, crystalline deposits are found within a vascular distribution and may extend from the posterior pole to the equator of the retina (Fig. 6.3). Later, these may progress to subretinal black ringlets that surround the crystals. The ringlets may coalesce and form large black geographic lesions. Visual acuity is generally good unless optic atrophy develops [27].

6.2  Disorders of Lipoprotein

Metabolism

6.2.1  The Gangliosidoses

The gangliosidoses are a group of inherited metabolic neurodegenerative disorders caused by a deficiency of specific proteins utilized in ganglioside degradation.