CHAPTER 28
Ocular Manifestations of Systemic Disease
This chapter focuses on systemic disorders with multiple types of ocular involvement. Systemic disorders associated with one primary ocular abnormality are discussed in other chapters in this volume (eg, Marfan syndrome is covered in Chapter 23, Childhood Cataracts and Other Pediatric Lens Disorders).
Diseases due to Chromosomal Abnormalities
Chromosomal disorders are classified as abnormalities in number (aneuploidy: trisomy or monosomy), structure (duplications, deletions, translocations, inversions, or rings), or type (autosomal or sex chromosome). Their incidence is approximately 1 in 150 live births.
Common trisomy syndromes are 13, 18, and 21. Turner syndrome is monosomy X. The most common deletions are 4p, 5p, 18p, and 18q. Table 28-1 describes the ocular findings associated with these disorders.
Table 28-1
Inborn Errors of Metabolism
Nearly 500 genes that contribute to inherited eye diseases have been identified. The overall incidence of inborn errors of metabolism is estimated to be 1 in 1400 births.
Inborn errors of metabolism are characterized by the genetic absence, either physical or functional, of 1 or more enzymes. Such errors may cause eye abnormalities in 1 of several ways: direct toxicity of abnormal metabolic products, accumulation of abnormal (or normal) metabolites, errors of synthetic pathways, or deficient production of energy. Inborn errors of metabolism are usually inherited as recessive disorders, either autosomal or X-linked. Germline mutations may also occur. Carriers of inborn errors of metabolism possess half the normal quantity of an enzyme, as would be expected in persons with 1 normal gene and 1 defective gene. This deficiency usually results in adequate metabolic function but subnormal serum levels. Measurements of enzyme levels in fetal cells obtained through amniocentesis may enable prenatal detection of many of these conditions.
The age of onset of eye problems in inborn errors of metabolism is variable; some are present at birth and others emerge in early childhood. Consultation with a geneticist is warranted for any patient with ocular findings that suggest an inborn error of metabolism. Table 28-2 summarizes the common ophthalmic manifestations of the major inborn errors of metabolism.
Table 28-2
Table 28-3
Inborn errors of metabolism can be categorized according to the processes and biochemical pathways affected by enzyme deficiencies (examples of specific disorders are in parentheses):
carbohydrate synthesis (galactosemia) amino acid metabolism (homocystinuria)
organic acid metabolism (methylmalonic aciduria) mitochondrial metabolism (Kearns-Sayre syndrome) urea cycle (ornithine transcarbamylase deficiency)
peroxisome function (adrenoleukodystrophy, Zellweger disease) steroid pathway (Smith-Lemli-Opitz syndrome)
lipid storage (Tay-Sachs disease, Gaucher disease) transport (cystinosis)
lysosomal storage (mucopolysaccharidoses, cystinosis, neuronal ceroid lipofuscinosis, galactosialidosis)
metal metabolism (Wilson disease)
These disorders can also be categorized according to the affected ocular structure.
Poll-The BT, Maillette de Buy Wenniger-Prick CL. The eye in metabolic diseases: clues to diagnosis. Eur J Paediatr Neurol. 2011;15(3):197–204.
Cornea
Metabolic diseases cloud the cornea via accumulation of a pathway product. If the product is produced in the cornea, the clouding may be found throughout the cornea. If the level of the product is elevated in the blood, the peripheral cornea alone may be involved. Diseases that affect the cornea include the mucopolysaccharidoses (MPS; types I H, I S, I H/S, II, IV, VI, and VII) (Fig 28-1), cystinosis, and Wilson disease. Cystinosis causes crystal-like deposits throughout the cornea and symptoms of photophobia. Wilson disease may present with a peripheral brown Kayser-Fleischer ring. See also Chapter 20.
Figure 28-1 Mucopolysaccharidosis VI. (Courtesy of Edward L. Raab, MD.)
Lens
In many multisystem metabolic diseases, cataracts occur (eg, as a feature of Smith-Lemli-Opitz syndrome and all the galactosemias). In galactokinase deficiency, cataracts may be the sole manifestation of the disease. Lens dislocation occurs in homocystinuria. Lens disorders are discussed in Chapter 23.
Retina
More than 400 inherited diseases involve the retina. The most common, retinitis pigmentosa (RP),
may occur as a primary defect in the photoreceptors or as a secondary event arising from sensitivity of the photoreceptors or the pigment epithelium to a generalized metabolic defect. Retinal degeneration is found in peroxisomal disorders (Zellweger disease, Refsum disease), lysosomal disorders (neuronal ceroid lipofuscinosis), and mitochondrial disorders (Kearns-Sayre syndrome).
Fovea
The appearance of a cherry-red spot in the macula is caused by loss of transparency of the perifoveal retina due to edema or deposition of abnormal material in the retinal ganglion cells. The fovea, which is very thin and almost devoid of ganglion cells (the site of abnormal material accumulation in storage disease), normally appears red to brown, depending on the patient’s race. With infiltration of the retinal ganglion cells, the thicker perifoveal retina becomes white and its color contrasts with that of the fovea, creating the cherry-red spot. Metabolic diseases that may cause a cherry-red spot include GM2 gangliosidosis type I (Tay-Sachs disease) and type II (Sandhoff disease), as well as NiemannPick disease. The cherry-red spot disappears over time as the intumescent ganglion cells die and optic atrophy develops. Therefore, the absence of a cherry-red spot should not be used to rule out a diagnosis, especially in older children.
Treatment of metabolic disorders
A variety of treatment options now exist for many previously untreatable metabolic disorders. These include enzyme replacement therapy, stem cell transplantation (bone marrow or umbilical cord blood), and dietary changes. Gene therapy is promising, and clinical trials have begun for some disorders. Usually, the earlier a patient is referred to a geneticist, the better the chance will be of a beneficial effect from such treatment.
Examples of treatable metabolic disorders with ocular findings are homocystinuria and cystinosis (see Chapters 20 and 23). Classic homocystinuria is caused by a deficiency of cystathionine β- synthase activity, which is usually detected shortly after birth if neonatal screening measures are employed. Dietary restriction of methionine and supplementation with folate, vitamin B6, vitamin B12, or betaine or a combination of these can markedly reduce plasma homocysteine levels and prevent disease progression. In most untreated patients with classic homocystinuria, cognitive impairment, ectopia lentis, and thrombotic events develop. The risk of these sequelae is greatly decreased by metabolic control. In patients with cystinosis, systemic cysteamine can ameliorate renal disease, and topical cysteamine eyedrops can prevent or reverse painful crystalline keratopathy.
Familial Oculorenal Syndromes
Lowe syndrome
Lowe syndrome (Lowe oculocerebrorenal syndrome) is an X-linked recessive disorder characterized by renal tubulopathy (Fanconi type) that occurs in the first year of life, leading to aminoaciduria, metabolic acidosis, proteinuria, and rickets. Affected children are severely hypotonic at birth, and cognitive impairment is common.
The most common eye defect is congenital bilateral cataract. The lenses are small, thick, and opaque and may demonstrate posterior lenticonus. Miotic pupils are frequent. Congenital glaucoma often develops. Surgery is frequently difficult, and cyclitic membrane formation and recalcitrant glaucoma are common following surgery. Mothers of affected children may have punctate snowflake opacities, oriented radially within the lens cortex, that indicate their carrier status.
Alport syndrome
Alport syndrome is usually inherited as an X-linked disorder. It is a disease of basement membranes