Central Nervous System Metabolic Abnormalities
Although a comprehensive description is beyond the scope of this chapter, the following discussion includes some of the major inherited metabolic diseases known to affect the CNS and retina (see Table 14-1). See BCSC Section 6, Pediatric Ophthalmology and Strabismus, for a listing of the ocular findings in inborn errors of metabolism.
Figure 14-3 Albinism. A, Color fundus photograph shows generalized fundus hypopigmentation. B, High-magnification color fundus photograph shows foveal hypoplasia. No foveal reflex or luteal pigment is evident. C, SD-OCT image shows the lack of a foveal pit. Eccentric fixation was also present, resulting in superior decentration of the scans.
(Parts A, B courtesy of Carl D. Regillo, MD; part C courtesy of David Browning, MD.)
Neuronal ceroid lipofuscinoses
The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive diseases caused by the accumulation of waxy lipopigments (eg, ceroid and lipofuscin) within the lysosomes of neurons and other cells. These disorders usually become evident in early childhood and are characterized by progressive dementia, seizures, and loss of vision associated with a pigmentary retinopathy in early-onset cases. A diagnosis can be made with genetic testing, in addition to a peripheral blood smear or biopsy of conjunctival or other tissues looking for the characteristic curvilinear, fingerprint-like or granular inclusions on electron microscopy. The infantile and juvenile types of NCLs are associated with pigmentary retinopathies (see Table 14-1). Ocular findings in infantile NCL include optic atrophy; macular pigmentary changes including bull’s-eye atrophic maculopathy, mottling of the fundus periphery, and retinal vascular attenuation; and reduced or absent ERG signals (Fig 14-4). The 2 adult forms of NCL do not have ocular manifestations.
Abetalipoproteinemia and vitamin A deficiency
Abetalipoproteinemia is an autosomal recessive disorder in which apolipoprotein B is not synthesized, which causes fat malabsorption, fat-soluble vitamin deficiencies, and retinal and spinocerebellar degeneration. Supplementation with vitamins A and E is needed to prevent or ameliorate the retinal degeneration. The most common form of vitamin A deficiency retinopathy occurs in patients who have undergone gastric bypass surgery for obesity or small-bowel resection for Crohn disease. These patients have malabsorption of fat-soluble vitamins and may develop a blind loop syndrome, in which an overgrowth of bacteria consumes vitamin A. Patients experience nyctalopia, and if the condition remains untreated, eventually demonstrate vision loss and diffuse, drusenlike spots similar to those observed in retinitis punctata albescens.
Figure 14-4 Color fundus photograph from a patient with Batten disease (juvenile neuronal ceroid lipofuscinosis) shows vascular attenuation and central retinal atrophy with mottled pigmentation and a wrinkled, cellophane-like surface.
(Used with permission from Hansen MS, Hove MN, Jensen H, Larsen M. Optical coherence tomography in juvenile neuronal ceroid lipofuscinosis. Retin Cases Brief Rep. 2016;10(2):137–139.)
Peroxisomal disorders and Refsum disease
The peroxisomal disorders are mostly autosomal recessive diseases caused by the dysfunction or absence of peroxisomes or peroxisomal enzymes, which leads to defective oxidation and accumulation of very-long-chain fatty acids. Zellweger syndrome is the prototype of peroxisomal diseases. Severe infantile-onset retinal degeneration is associated with hypotonia, psychomotor impairment, seizures, characteristic facies, renal cysts, and hepatic interstitial fibrosis. Death usually occurs in infancy. Patients with neonatal adrenoleukodystrophy also present in infancy but generally survive until the age of 7–10 years (Fig 14-5).
Similar but less severe findings are present in infantile Refsum disease, which is characterized by pigmentary retinopathy with reduced or extinguished ERG signals, cerebellar ataxia, polyneuropathy, anosmia, hearing loss, and cardiomyopathy. Diagnosis is made by demonstrating elevated plasma levels of phytanic acid or reduced phytanic acid oxidase activity in cultured fibroblasts. Dietary restriction of phytanic acid precursors may slow or stabilize the neuropathy but typically not the retinal degeneration.
The systemic mucopolysaccharidoses (MPSs) are caused by inherited defects in catabolic lysosomal enzymes that degrade the glycosaminoglycans dermatan sulfate, keratan sulfate, and heparan sulfate. The MPSs are transmitted as autosomal recessive traits except for type II, which is an X-linked recessive disorder (see Table 14-1).
Only those MPSs in which heparan sulfate is stored are associated with retinal dystrophy. These include MPS type I H (Hurler syndrome) and MPS type I S (Scheie syndrome), the clinical features of which include coarse facies, cognitive disabilities, corneal clouding, and retinal degeneration. The retinal pigmentary changes may be subtle, but the ERG response is abnormal. MPS type II (Hunter syndrome) also features pigmentary retinopathy but corneal clouding, if present, is only mild; patients have coarse facies and short stature and may show cognitive disabilities. In MPS type III (Sanfilippo syndrome), somatic stigmata are mild, but pigmentary retinopathy is severe.
Figure 14-5 Neonatal adrenoleukodystrophy. Color fundus photograph shows retinal arteriolar attenuation, diffuse pigmentary alterations, and mild optic atrophy.
(Courtesy of Mark W. Johnson, MD.)
Other lysosomal metabolic disorders
Tay-Sachs disease (GM2 gangliosidosis type I), caused by a deficient subunit A of hexosaminidase A, is the most common ganglioside storage disease. Glycolipid accumulation in the brain and retina causes cognitive disability and blindness, and death generally occurs between the ages of 2 and 5 years. Ganglion cells surrounding the fovea become filled with ganglioside and appear grayish or white, causing a cherry-red spot (Fig 14-6).
The chronic nonneuronopathic adult form of Gaucher disease does not have cerebral involvement. This disease is characterized by large accumulations of glucosylceramide in the liver, spleen, lymph nodes, skin, and bone marrow. Some patients have a cherry-red spot; others show whitish superficial lesions in the midperiphery of the fundus. Spectral-domain optical coherence tomography (SD-OCT) analysis demonstrates multiple characteristic hyperreflective lesions located along the retinal surface.
The various types of Niemann-Pick disease are caused by the absence of different sphingomyelinase isoenzymes. Type A (acute neuronopathic) Niemann-Pick disease shows a cherry-red spot in about 50% of cases. Type B (chronic) Niemann-Pick disease, also known as sea-blue histiocyte syndrome, is the mildest, and although there is no functional involvement of the CNS, patients have a macular halo that is considered diagnostic (Fig 14-7).
Fabry disease (angiokeratoma corporis diffusum) is an X-linked condition caused by mutations in the gene encoding alpha-galactosidase A. Ceramide trihexoside accumulates in the smooth muscle of blood vessels in the kidneys, skin, gastrointestinal tract, CNS, heart, and reticuloendothelial system. Ocular signs include corneal verticillata (whorls), tortuous conjunctival vessels, tortuous and dilated retinal vessels, and lens changes. Tortuosity of conjunctival and retinal vessels is also characteristic of fucosidosis, a rare lysosomal storage disorder caused by buildup of complex sugars due to reduced or absent activity of the alpha-l-fucosidase enzyme.
Figure 14-6 Tay-Sachs disease. Color fundus photograph shows a cherry-red spot.
Figure 14-7 Chronic Niemann-Pick disease. Color fundus photograph shows a macular halo.
(Courtesy of Mark W. Johnson, MD.)
Gregory-Evans K, Pennesi ME, Weleber RG. Retinitis pigmentosa and allied disorders. In: Schachat AP, Wilkinson CP, Hinton DR, Sadda SR, Wiedemann P, eds. Ryan’s Retina. 6th ed. Philadelphia: Elsevier/Saunders; 2018:861–935.
Haltia M. The neuronal ceroid-lipofuscinoses: from past to present. Biochim Biophys Acta. 2006;1762(10):850–856.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.