LCA is an autosomal recessive syndrome characterized by significantly reduced vision before age one, nystagmus, paradoxical pupillary reactivity, and retinal degeneration. This syndrome has a prevalence of 3:100,000 children and is a common cause of congenital nystagmus. Six LCA-causing genes have been identified, which account for approximately one half of the cases.¹ These genes are expressed preferentially in the retina or the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photoreceptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). The clinical appearance is varying with fundus findings ranging from a retinitis pigmentosa picture with bony spicules to a salt and pepper appearance (Fig. 22-1). Electroretinography (ERG) demonstrates a markedly reduced or nonrecordable scotopic and photopic response, confirming the diagnosis. Although no therapy is presently available, promising gene-based interventions have demonstrated long-term rescue of vision as assessed by psychophysical, behavioral, and molecular biology studies. In a naturally occurring LCA animal model, the RPE65-/- dog, recombinant adenoassociated virus carrying wild-type RPE65 successfully restored visual function.²

Figure 22-1 Ophthalmoscopic appearance of the retina in a patient with Leber’s congenital amaurosis caused by mutations in CRB1.

(Courtesy of I. H. Maumenee.)

Achromatopsia is a rare retinal disorder characterized by a complete absence of cone photoreceptor function. In accordance with the trichromatic theory of vision, individuals with normal color vision can match any color with a combination of three primary colors: red, green, and blue. Dichromats who are missing either the red (protanopes) or green (deuteranopes), but retain the blue cone function, can only match colors with two primary colors. The red (OPN1LW, opsin 1, long wave sensitive) and green (OPN1MW, opsin 1 medium wave sensitive) photopigments are encoded on the long arm of the X chromosome and, as such, these disorders are transmitted in a pattern of X-linked inheritance. The blue (OPN1SW, opsin 1, short wave sensitive) photopigment is encoded on chromosome 7. Achromats present in infancy with reduced vision, photophobia, total color blindness, nystagmus, and a normal-appearing retina. Achromatopsia refers to a spectrum of disease encompassing complete achromatopsia (rod monochromacy), in which there are no cones; atypical rod monochromacy, in which there are some functioning cones; and blue cone monochromacy, where the red and green photopigments are absent but the blue photopigment is functional. Psychophysical testing in such patients must be performed after age 10 in order to get reproducible results. Genes associated with achromatopsia include CNGA3³ and CNGB3,⁴ encoding the α and β subunits of the cone cyclic nucleotide-gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors. A third gene identified in achromatopsia is GNAT2,⁵ encoding the cone specific α unit of transducin, a G protein of the phototransduction cascade.

Aniridia is a syndrome in which the most prominent manifestation is absence or hypoplasia of the iris. Importantly, visual acuity is reduced due to hypoplasia of the fovea, macula, or optic nerve. Patients present with reduced visual acuity, elevated intraocular pressure, and nystagmus and may develop cataract, glaucoma, keratopathy, strabismus, and amblyopia. Aniridia is caused by mutations in PAX6, a homeobox gene on chromosome 11.⁶ The homeobox encodes the homeodomain, a protein domain that binds DNA and regulates the transcription of other genes. Aniridia is inherited as an autosomal dominant disorder. WAGR syndrome consists of Wilm’s tumor, aniridia, genitourinary abnormalities, and retardation, resulting from a deletion on chromosome 11p.

Albinism is traditionally divided into oculocutaneous albinism and ocular albinism. Oculocutaneous albinism is autosomal recessive and has been divided into tyrosinase-positive and -negative forms. Tyrosinase catalyzes three steps in a series of reactions in the melanosome that lead to the formation of melanin from its precursor tyrosine. Major oculocutaneous albinism syndromes include Hermansky-Pudlak syndrome and Chediak-Higashi syndrome, which are inherited in autosomal recessive manner. Nettleship-Falls ocular albinism is an X-linked recessive disorder characterized by reduced visual acuity, congenital nystagmus, transillumination defects of the iris (Fig. 22-2), hypopigmentation of the uveal tract and retinal pigment epithelium, hypoplasia of the fovea, and abnormal decussation of optic nerve fibers through the chiasm. Strabismus and refractive abnormalities are common. Ocular albinism is caused by mutations in OA1, a member of the G protein-coupled receptor superfamily.⁷

Figure 22-2 In a patient with albinism, transillumination of the globe demonstrates the absence of pigment in the iris (left). On ophthalmoscopic examination of the retina, the lack of pigmentation in the retinal pigment epithelium allows easy visualization of the choroidal vessels (right).

(Courtesy of I. H. Maumenee.)

Hereditary vitreoretinopathies are characterized by degenerative changes involving the vitreous and retina. These include familial exudative vitreoretinopathy, Goldmann-Favre syndrome, Stickler’s syndrome, Knobloch’s syndrome, and Norrie disease. Familial exudative vitreoretinopathy (FEVR) has features similar to retinopathy of prematurity but without premature birth or supplemental oxygen. This autosomal dominant disorder is caused by mutations in the frizzled-4 gene (FZD4)⁸ and is characterized by peripheral retinal vascular nonperfusion, exudative retinal detachment, and proliferative, cicatricial vitreoretinopathy. With severe loss of vision, patients develop nystagmus and strabismus. Goldmann-Favre syndrome is an autosomal recessive disorder caused by mutations in the nuclear receptor gene NR2E3 with characteristic features of retinitis pigmentosa along with central and peripheral retinoschisis, a splitting of the retina. Stickler’s syndrome, a progressive hereditary arthro-ophthalmopathy, is characterized by high myopia, vitreous degeneration, and retinal detachment (Fig. 22-3) in association with orofacial abnormalities such as Pierre-Robin sequence and musculoskeletal abnormalities such as arthritis, scoliosis, and arachnodactyly. It is inherited as an autosomal dominant disorder and caused by mutations in type II collagen (COL2A1). Knobloch’s syndrome is characterized by high myopia, vitroretinal degeneration with retinal detachment, and occipital encephalocele and is caused by a mutation in collagen XVIII (COL18A1). Norrie’s disease is characterized by mental retardation and bilateral retinal detachment presenting early in life. It is inherited as an X-linked disorder caused by mutations in the Norrie gene, which is thought to interact with the FZD4 gene.

Figure 22-3 Fundus appearance of a total retinal detachment in a patient with Stickler’s syndrome.

(Courtesy of I. H. Maumenee.)

RETINAL DISEASES—ONSET IN CHILDHOOD AND ADULTHOOD

Retinitis pigmentosa (RP) encompasses a variety of disorders that primarily affect rod photoreceptors. Although a pigmentary retinopathy may occur as a feature of a variety of multisystem diseases discussed at the end of the chapter, it may also occur as an isolated disorder of the retina. Initial vision loss in RP occurs in the midperipheral visual field and initial retinal pathology in the postequatorial fundus. In contrast, cone dystrophies refer to those photoreceptor disorders primarily affecting cones and initially involving the macula. There is considerable overlap between these entities. Inability to see as clearly in dim light as in bright light (nyctalopia) is the initial symptom of the rod dystrophies, followed by loss of peripheral vision. The fundus initially has a gray discoloration at the level of the retinal pigment epithelium (RPE) in areas corresponding to vision loss. With time, pigmented cells migrate into the retina aggregating around blood vessels leading to the characteristic bone spicule appearance and a “waxy” pallor of the optic nerve.

The most common hereditary form of RP is autosomal recessive (60%), followed by autosomal dominant (10% to 25%) and X-linked (5% to 18%). The X-linked and recessive forms are more severe than autosomal dominant RP. The first gene determined to be mutated in RP was rhodopsin.⁹ Other genes include peripherin, tissue inhibitor of metalloproteinase, and geronyl-geronyl transferase. More than 20 genes causing RP have been identified.

In contrast to retinitis pigmentosa, patients with cone dystrophies present with symptoms of blurred vision and inability to see as clearly in bright light as in dim light (hemeralopia). On examination, patients have central loss of vision which manifests as a reduction in visual acuity or a central scotoma on visual field testing and loss of color vision due to degenerative disease of the cone photoreceptors. In early stages, it may be difficult to diagnose because of a normal appearing ophthalmoscopic examination. Patients eventually develop a pigmentary degeneration of the macula, often described as a bull’s eye maculopathy. In many instances, optic pallor develops, leading one to suspect optic nerve disease rather than retinal disease. The ability to diagnose cone dystrophies in the early stages prior to ophthalmoscopically evident retinal pathology has been advanced by the use of multifocal ERG. Well-known toxicities associated with degenerative cone disease include chloroquine and digoxin.

Cone degenerations may be inherited in an autosomal or X-linked pattern. Genes identified as causing cone degenerations include guanylate cyclase activator-1A (GUCA1A), retinitis pigmentosa GTPase regulator (RPGR), and the CRX gene, a homeobox gene expressed in photoreceptors.

Juvenile retinoschisis is an X-linked recessive disorder that manifests in childhood with reduction in visual acuity. The characteristic macular abnormality is a cystlike appearance with spoke like extensions from the fovea. It is highly penetrant in males, whereas carrier females rarely show macular pathology. It is caused by mutations that lead to the pathological development of a schisis or splitting of the retina in the nerve fiber layer. The RS gene is implicated in cell-cell adhesion and phospholipid binding.¹⁰

Stargardt’s disease is a storage disease of the retinal pigment epithelium that leads to bilateral progressive loss of central visual acuity. Stargardt’s disease is an autosomal recessive disorder caused by mutations in the ABCR4 gene, encoding an ATP-binding cassette (ABC) transporter.¹¹ Patients often present in the second decade of life with unexplained reduction in visual acuity. Features include subretinal yellow pisiform flecks, referred to as fundus flavimaculatus, and macular changes including increased granularity and a “beaten metal” appearance. ERG shows a moderately reduced photopic response and a nearly normal scotopic response. Fluorescein angiography is important in establishing the diagnosis, demonstrating a “silent choroid sign,” which refers to the darkened appearance of the choroid due to blockage by diffuse storage of material at the RPE (Fig. 22-4).

Figure 22-4 Fluorescein angiogram is performed by injecting fluorescein dye into the vein of a patient and taking a series of photographs as the dye passes through the retinal and choroidal vasculature. In a normal ocular fundus, a “background” of fluorescence emanating form the choroid is observed (left). In a patient with Stargardt’s disease (right), fluorescence is “blocked” by deposits in the RPE and referred to as a “dark choroid.” The arrowhead in the right photograph indicates an area of early and late central hyperfluorescence in a bull’s-eye pattern.

(Right, reprinted with permission from Margalit E, Sunness JS, Green WR, et al. Stargardt disease in a patient with retinoblastoma. Arch Ophthalmol 2003; 121:1643-1646. Copyright 2003 American Medical Association. All rights reserved.)

Best’s vitelliform macular dystrophy is an autosomal dominant disease characterized by the development of an egg-yellow, slightly raised lesion in the macula that is usually 1 to 3 disc diameters in size. Patients may experience blurred central vision and metamorphopsia. Although the fundus appearance is often dramatic, the visual acuity is often better than 20/40. An abnormal electro-oculogram, which measures the electrical potential across the retinal pigment epithelium, is particularly helpful in the diagnosis of patients. The macular abnormality evolves with time from an “egg yolk” appearance to a “scrambled egg” appearance to a late cicatricial stage. Mutations in VMD2, a gene encoding the bestrophin protein, have been associated with Best’s disease. Bestrophin localizes to the basolateral plasma membrane of RPE cells ¹² and is likely involved in chloride ion conductance.

Congenital stationary night blindness (CSNB) describes a group of retinal diseases characterized by nyctalopia without progressive retinal degeneration. CSNB may be inherited in an autosomal dominant or X-linked pattern. Two types of ERG abnormalities that may be observed in different subtypes of CSNB are (1) a reduced scotopic ERG waveform in the dark adapted ERG or (2) absence of the b-wave on a dark-adapted bright-flash ERG referred to as a “negative” waveform. Autosomal dominant CSNB has been associated with mutations in either the α or β subunit of rod cGMP phosphodiesterase as well as the rhodopsin gene. X-linked CSNB patients have a myopic tigroid-appearing fundus and congenital nystagmus. The visual acuity is typically better than 20/40. It is caused by mutations in NYX, encoding nyctalopin, and a retina-specific calcium channel α1 subunit gene (CACNA1F).¹³ Although the typical CSNB fundus doe not have any significant pathologicalfeatures, two types of CSNB stand out. Fundus albipunctatus is a type of CSNB inherited in an autosomal recessive pattern that shows distinct, impressive white, round flecks scattered throughout the fundus. Oguchi’s disease is inherited as an autosomal recessive disorder in which the macular retina has an abnormally dark appearance compared with the rest of the fundus, an appearance that disappears with dark adaptation. It is caused by mutations in the arrestin gene.

Choroideremia is an X-linked progressive chorioretinal degeneration characterized by progressive nyctalopia and peripheral vision loss. The fundus undergoes progressive atrophy of the choriocapillaris, the retinal pigment epithelium, and photoreceptors that gradually encroaches on the macula. The appearance is very similar to gyrate atrophy of the retina and choroid. Choroideremia is caused by a mutation in the Rab escort protein-1 gene (REP-1) of geranylgeranyl transferase. This enzyme catalyzes the addition of 20 carbon groups to two cysteines at the carboxyl terminus of Rab proteins.

OPTIC NERVE DISEASES—CONGENITAL

Optic nerve hypoplasia may be observed with normal visual acuity in association with a subtle visual field defect or manifest with profound visual loss (Fig. 22-5). In childhood, optic nerve hypoplasia may manifest as a unilateral decrease in vision diagnosed initially as amblyopia or bilateral decreased vision in infancy diagnosed initially as congenital nystagmus. In these instances, it is important to recognize its association with midline forebrain abnormalities, which can result in pituitary hormone deficiencies and even sudden death.

Figure 22-5 The optic nerve on the left is hypoplastic. For comparison, a normal optic nerve is shown on the right. Both optic nerves are from the right eye.

Both teratogenic and genetic etiologies have been described. Recognized teratogens associated with optic nerve hypoplasia include alcohol, quinine, and anticonvulsants. Maternal insulin-dependent diabetes mellitus is associated with superior segmental optic nerve hypoplasia as well. Optic nerve hypoplasia has also been observed in association with many ocular and systemic syndromes including chromosomal duplications and deletions. Septo-optic dysplasia (de Morsier’s syndrome) refers to the association of hypoplasia of the anterior visual pathways, absence of the septum pellucidum, and thinning or agenesis of the corpus callosum. Although familial cases have been reported, most cases are sporadic. Mutations in the homeobox containing transcription factor, HESX1, have been implicated with homozygous inheritance, causing the more severe phenotype, and heterozygous inheritance, causing a mild phenotype.^14,¹⁵ Mutations in PAX6 have been observed with a variety of optic nerve abnormalities including coloboma, morning glory disc anomaly, optic-nerve hypoplasia/aplasia, and persistent hyperplastic primary vitreous.¹⁶

Papillorenal syndrome (renal-coloboma syndrome) is a primary dysgenesis that causes vascular abnormalities predominantly affecting the eye, kidney, and urinary tract. The characteristic optic nerve finding in papillorenal syndrome is an absence or attenuation of the central retinal vessels within the optic nerves, with multiple compensatory cilioretinal vessels. Although the abnormality in these patients has been referred to as a coloboma, it is not a true coloboma arising from failure of closure of the optic nerve fissure with superonasal displacement of the central retinal vessels.^17,¹⁸ Papillorenal syndrome is inherited in an autosomal dominant pattern. Mutations in PAX2 have been identified in papillorenal syndrome,¹⁹ but it is a heterogeneous disease. Patients should undergo renal function testing including serum creatinine and urea nitrogen measurements, urinalysis to test for microalbuminuria, and renal ultrasound.

OPTIC NERVE—ONSET IN CHILDHOOD AND ADULTHOOD

Autosomal dominant optic atrophy is characterized by bilateral insidious vision loss often manifesting in the first or second decade of life. It is inherited in an autosomal dominant pattern with high penetrance. OPA1, located on the long arm of chromosome 3, accounts for the majority of cases, although there is evidence of genetic heterogeneity. The protein is a dynamin-related GTPase targeted to mitochondria, further demonstrating a role for mitochondria in retinal ganglion cell pathophysiology.^20,²¹

At presentation, the visual acuity is typically 20/40 to 20/60, bilateral, and symmetrical. There is an insidious progression of vision loss, although final visual acuity may vary from 20/20 to no light perception. Most individuals retain a visual acuity of 20/40 to 20/200. Color vision testing has demonstrated a characteristic tritanopic-type deficiency, although a generalized dyschromatopsia is most common. Visual field defects include central and cecocentral scotomas. Optic atrophy is present, often localized to the temporal portion of the optic nerve (Fig. 22-6). Other than sensineural hearing loss, neurological or systemic findings are uncommon.

Figure 22-6 A 10-year-old boy presents with a visual acuity of 20/40, bilateral central scotomas, and bilateral temporal optic atrophy (right and left eyes). His father has similar findings. Genetic testing revealed a mutation in OPA1.

The differential diagnosis includes nutritional deficiency, toxic optic neuropathy, and macular dystrophy. Diagnosis is based on family history and clinical examination. Genetic testing has not become widely available for this disorder. Unfortunately, no treatments are available at the present time to prevent vision loss, arrest the progression of vision loss, or restore vision.

Wolfram’s disease is an autosomal recessive disease caused by mutations in WFS1 which encodes an integral membrane glycoprotein that localizes primarily in the endoplasmic reticulum.²² The most consistent criteria for diagnosis of this syndrome are juvenile-onset diabetes mellitus and optic atrophy. However, other findings include diabetes insipidus and sensory neural hearing loss. The constellation of findings has led to the acronym DIDMOAD: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness. Less commonly recognized features include central apnea and neurogenic upper airway collapse, together precipitating primary respiratory failure, startle myoclonus, axial rigidity, and Parinaud’s syndrome.²³

Behr’s disease is an autosomal recessive syndrome of optic atrophy, beginning in the first decade of life, associated with pyramidal tract signs, ataxia, mental retardation, nystagmus, urinary incontinence, and pes cavus. Behr’s disease may represent a phenotype that is common to several genetic disorders that are likely metabolic in origin. Methylglutaconic aciduria, diagnosed by increased amounts of 3-methylglutaconic and 3-methylglutaric acid in urine, may manifest with this constellation of findings.²⁴

X-linked optic atrophy patients present with vision loss in early childhood, which may be progressive. This rare disease is often associated with other neurological findings, including ataxia, tremor, sensineural deafness, and polyneuropathy.²⁵

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy with bilateral vision loss, typically occurring in young men.

LHON is caused by point mutations in the mitochondrial genome at nucleotide positions 3460,²⁶ 11778,^27,²⁸ and 14484²⁹ in genes encoding subunits of complex I of the respiratory chain, with the 11778 mutation accounting for the majority of cases. As mitochondria are only transmitted by the mother to all offspring, the typical rules of mendelian inheritance do not apply. All children of maternal carriers are at risk of vision loss, although male children are at greater risk of vision loss than their female siblings. The offspring of male carriers are not at risk for vision loss.

Vision loss typically begins painlessly in one eye, progressively worsening over a few weeks. Although some individuals subjectively describe visual loss as sudden and complete, others describe progression over the course of a few weeks. Almost all patients develop vision loss in the fellow eye, usually within 6 months of the vision loss in the first eye. Typically, no other symptoms occur at the time of vision loss.

Visual acuity is commonly worse than 20/200 in each eye with bilateral central scotomas. On ophthalmoscopy, the optic nerve may appear normal or have a characteristic abnormality that has been described as a triad of circumpapillary telangiectasia (Fig. 22-7), swelling of the nerve fiber layer around the disc, and absence of leakage on fluorescein angiography. The optic nerve progresses to optic atrophy with nonglaucomatous cupping, pallor, and arteriole attenuation.

Figure 22-7 The right optic nerve from a patient with Leber’s hereditary optic neuropathy demonstrates circumpapillary telangiectasia and a prominent peripapillary nerve fiber layer.

In rare individuals, associated neurological abnormalities may be present such as pathological reflexes, mild cerebellar ataxia, tremor, movement disorders, muscle wasting, and distal sensory neuropathy. In a few pedigrees, more severe neurological deficits may be present such as dystonia, spasticity, and encephalopathic episodes. In addition to neurological abnormalities, some patients may have cardiac conduction defects, and patients should undergo electrocardiography.

Patients generally present with unilateral acute or subacute vision loss. The differential diagnosis includes optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, infiltrative optic neuropathy, and neoplasm. Definitive diagnosis is made by genetic testing. The prognosis for restoration of vision is typically poor for these individuals. Nevertheless, some individuals may recover vision spontaneously, even years later. Unfortunately, no treatments are available at the present time to prevent vision loss, arrest the progression of vision loss, or restore vision.

RETINOPATHY AND OPTIC NEUROPATHY ASSOCIATED WITH SYSTEMIC AND NEURODEGENERATIVE DISEASE

A variety of genetic disorders lead to vision loss in addition to other systemic and neurological symptoms. These include metabolic defects of amino acid, protein, and lipoprotein metabolism; lysosomal storage diseases; lipid metabolic disorders; peroxisomal diseases; mitochondrial genetic disease; neuronal ceroid lipofuscinosis; other neurodegenerative disorders; and a variety of disorders with prominent systemic manifestations.

Disorders of amino acid, protein, and lipoprotein metabolism may lead to blindness from retinal degeneration. Gyrate atrophy of the retina and choroid is an autosomal recessive disease due to a defect in ornithine aminotransferase leading to serum hyperornithemia. It leads to geographic and round-shaped areas of chorioretinal atrophy that begin peripherally and progress centrally. Cystinosis is an autosomal recessive disease characterized by progressive renal failure, pigmentary retinopathy, and growth retardation due to a deposition of cysteine crystals throughout the body. It is caused by a lysosomal defect preventing transport of cysteine crystals from the lysosome to the cytosol. Cysteine crystals are also deposited in the cornea leading to significant photophobia. Methylmalonic aciduria and homocystinuria result in a pigmentary retinopathy and optic nerve pallor due to an abnormality in cobalamin metabolism. Abetalipoproteinemia is an autosomal recessive disorder associated with a pigmentary retinopathy in which patients have fat malabsorption, progressive ataxia, and abnormal plasma lipids due to deficient beta lipoproteins and chylomicons.

Lysosomal storage diseases are caused by enzymatic defects that lead to an accumulation of partially degraded intermediates in cells, tissues, and organs leading to dysfunction. They are generally inherited in an autosomal recessive manner. Mucopolysaccharidoses are caused by defects in specific lysosomal enzymes involved in the degradation of glycosaminoglycans or mucopolysaccharides. General features include facial dysmorphic changes, mental retardation, corneal clouding (Fig. 22-8), and retinal degeneration. Optic disc swelling and optic atrophy are also features of mucopolysaccharidoses. Mucopolysaccharidoses associated with ophthalmological features include Hurler’s syndrome, Scheie’s syndrome, Hunter’s syndrome, Sanfilippo’s syndrome, and Maroteaux-Lamy syndrome. Sialadoses are characterized by the progressive lysosomal storage of sialidated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. There is a progressive accumulation and excretion of sialic acid. Patients develop corneal clouding and a cherry-red spot in the macula. Mucolipidoses have similar features to mucopolysaccharidoses but without mucopolysacchariduria. Patients have a Hurler-like facies, hepatosplenomegaly, and a thickened skull. Major subtypes of mucolipidoses include mucolipidosis II (I cell disease), mucolipidosis III, and mucolipidosis IV. Mucolipidosis IV has the most prominent ocular features including corneal clouding and retinal degeneration in addition to hypotonia and psychomotor retardation. Sphingolipidoses are due to an accumulation of glycosphingolipids, an abundant component of neurons. These disorders include the gangliosidoses (GM₂ gangliosidoses [type 1: Tay-Sachs disease; type 2: Sandhoff’s disease] and GM₁ gangliosidoses [Gaucher’s disease, Farber’s disease, Fabry’s disease, and Neimann-Pick disease]). Tay-Sachs and Sandhoff diseases are notable for the development of a cherry-red spot in the macula in which there is a deep red spot in the fovea surrounded by a ring of opacified retina. In addition, patients have hepatosplenomegaly and skeletal dysostosis.

Figure 22-8 Corneal clouding is a prominent feature of many lysosomal storage diseases, particularly mucopolysaccharidoses. The picture is from a patient with Maroteaux-Lamy syndrome.

(Courtesy of I. H. Maumenee).

Metachromatic leukodystrophy (MLD) is a lipid metabolic disorder caused by mutations in the arylsulfatase A gene. There are five allelic forms, including late infantile, adult partial cerebroside sulfate deficiency, and pseudo-arylsulfatase deficiency.³⁰ On histopathological staining, there is a metachromatic staining of abnormally stored galactosphingosulfatides in central nervous system white matter. The late infantile form is the most common form of MLD, manifesting in the second year of life with gait disturbance and muscle rigidity. This is followed by progressive mental deterioration and convulsions. A cherry-red spot may be present in the macula and optic atrophy may develop.

Peroxisomal disorders are rare disorders affecting multiple tissues, including the eye. These diseases have overlapping clinical manifestations and are classified into two categories. In peroxisome biogenesis disorders, peroxisomal assembly is defective due to abnormal localization of proteins normally targeted to the peroxisomes. This results in severe diseases that commonly affect the retina: Zellweger’s syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum’s disease (IRD). Although these three diseases were described as separate entities before the underlying peroxisomal defect was defined, identification of the underlying molecular defects and better understanding of the resulting biochemical defects, suggest that all three are parts of one spectrum in which ZS represents the more severe form, NALD an intermediate severity, and IRD the least severe. In the most severe form of ZS, children present with seizures, hypotonia, and developmental delay. Ophthalmological abnormalities include cataracts, glaucoma, corneal clouding, pigmentary retinal degeneration, and optic atrophy. In IRD, patients have reduced cognition, hearing loss, and a pigmentary retinopathy. As in classic Refsum’s disease, they have elevated phytanic acid and cholesterol but differ because of the elevation of very-long-chain fatty acids.

A second group of peroxisomal disorders are due to gene defects that result in abnormal peroxisome function without affecting its assembly. This group includes entities such as X-linked adrenoleukodystrophy, primary hyperoxaluria type 1, and classic Refsum’s disease. XLA is characterized by an accumulation of very-long-chain fatty acids of 22 to 30 carbons. X-linked adrenoleukodystrophy may manifest in childhood with gait disturbance and intellectual deterioration between the ages of 5 and 8. There is impressive inflammation of white matter and demyelination. In latter stages of the disease, patients develop vision loss with optic atrophy. The adult-onset variety of X-linked adrenoleukodystrophy is referred to as adrenomyeloneuropathy. X-linked adrenoleukodystrophy is caused by mutations in ABCD1, a member of the ATP-binding cassette (ABC) transporter superfamily that contains membrane proteins that translocate a wide variety of substrates across extracellular and intracellular membranes. Primary hyperoxaluria type 1 is an autosomal recessive disorder caused by a defect in the enzyme alanine glyoxylate aminotransferase and characterized by renal failure and elevated intracranial pressure. Patients develop a hyperplasia of the retinal pigment epithelium due to deposition of calcium oxalate crystals. Classic Refsum’s disease is characterized by a pigmentary retinopathy, polyneuropathy, hearing loss, icthyosis, and ataxia due to a defect in phytanoyl-CoA hydroxylase (PAHX) or peroxin-7 (PEX7), which impair the degradation of phytanic acid.

Mitochondrial disorders in addition to LHON include NARP, MELAS, and Kearns-Sayre syndrome. NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) is caused by a T-to-G point mutation in nucleotide 8993 of mtDNA, which results in a substitution of a highly conserved leucine by an arginine residue in the mitochondrial ATPase 6 gene.³¹ As the acronym implies, clinical features include migraine, sensory neuropathy, proximal muscle weakness, ataxia, seizures, dementia, and pigmentary retinopathy (Fig. 22-9). The retinal degeneration in NARP may manifest as a cone-rod dystrophy, a progressive cone dystrophy, a bull’s eye maculopathy, or rod-cone type of retinal dystrophy. The severity of NARP appears to correlate with the burden of mutated mitochondria within the population of mitochondria in the cell. The 8993 mutation also causes maternally inherited Leigh disease.³²