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.
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.
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.
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.
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).
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 Niemann-Pick 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.
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 is usually inherited as an X-linked disorder. It is a disease of basement membranes that causes progressive renal failure, deafness, anterior lenticonus or anterior subcapsular cataract, posterior polymorphous dystrophy, and fleck retinopathy. Hematuria begins in childhood. Hypertension and kidney failure occur late in the course of the disease.
Senior-Loken syndrome is an autosomal recessive disease characterized by nephronophthisis, renal failure, and a pigmentary retinal degeneration similar to that of Leber congenital amaurosis (LCA), with a flat electroretinogram (ERG). Children who have received a diagnosis of LCA should undergo renal function studies to rule out Senior-Loken syndrome.
The phakomatoses, or neurocutaneous syndromes, are a group of disorders characterized by multiple lesions of 1 or more histologic types that are found in 2 or more organ systems, including the skin and central nervous system (CNS). The lesions are commonly multiorgan hamartomas. Ocular involvement is frequent and may constitute an important source of morbidity as well as provide diagnostic information. Four major disorders have traditionally been designated phakomatoses, all of which have important ocular manifestations:
- neurofibromatosis (von Recklinghausen disease)
- tuberous sclerosis (Bourneville disease)
- angiomatosis of the retina and cerebellum (von Hippel–Lindau disease)
- encephalofacial or encephalotrigeminal angiomatosis (Sturge-Weber syndrome)
Other conditions sometimes classified as phakomatoses include
- ataxia-telangiectasia (Louis-Bar syndrome)
- incontinentia pigmenti (Bloch-Sulzberger syndrome)
- racemose angioma (Wyburn-Mason syndrome)
- Klippel-Trénaunay-Weber syndrome
Patients with neurofibromatosis (NF) manifest characteristic lesions composed of melanocytes or neuroglial cells, both of which are derivatives of neural crest mesenchyme. Although the melanocytic and glial lesions in NF are often called hamartomas, this designation is questionable because most lesions do not become evident until years after birth and many are histologically indistinguishable from low-grade neoplasms originating in the same tissues. NF has 2 forms that are distinguished by differences in genetics, diagnostic criteria, morbidity, and treatment.
Neurofibromatosis 1 (NF1) is the most common single-gene disorder affecting the nervous system. It affects 1 in 3000 to 3500 people and has autosomal dominant inheritance with virtually 100% penetrance. Approximately 50% of cases are sporadic, presumably the result of new mutations. The genetic locus of NF1 is on the long arm of chromosome 17 (17q11.2). The NF1 gene is associated with neurofibromin, which is involved in regulation of cellular proliferation and tumor suppression.
Melanocytic lesions Almost all adults with NF1 have melanocytic lesions involving both the skin and the eye. Café-au-lait spots, the most common cutaneous expression, appear clinically as flat, sharply demarcated, uniformly hyperpigmented macules of varying size and shape. At least a few are usually present at birth; their number and size increase during the first decade of life. Many unaffected individuals have 1–3 café-au-lait spots, but greater numbers are rare except in association with NF. Clusters of small café-au-lait spots, or freckling, in the axillary or inguinal regions are particularly characteristic of NF1.
Melanocytic lesions of the uveal tract are common ocular manifestations of NF. Iris lesions are small (usually <1 mm), sharply demarcated, dome-shaped excrescences known as Lisch nodules (Fig 28-2). Most Lisch nodules develop between ages 5 and 10 years and are present in nearly all affected adults. An affected adult’s eye typically has dozens.
Choroidal lesions occur in one-third to one-half of adults with NF1. These hyperpigmented lesions are flat with indistinct borders. Their number varies from 1 to 20 per eye, and each lesion is typically 1–2 times the size of the optic disc. These lesions may be difficult to visualize by conventional fundus examination; near-infrared reflectance imaging has a high sensitivity for detection.
Neither the vision nor the health of the eye is affected by these melanocytic lesions, regardless of their extent. Persons with NF1 are thought to be predisposed to uveal melanoma and to several other malignant neoplasms. However, the prevalence of iris (especially choroidal) tumors is still low.
Glial cell lesions The most common neuroglial lesions in NF1 are nodular and subcutaneous neurofibromas, plexiform neurofibromas, and optic pathway gliomas.
NODULAR NEUROFIBROMAS Among lesions of neuroglial origin in NF1, nodular cutaneous and subcutaneous neurofibromas, or fibroma molluscum, are by far the most common. These lesions are soft, often pedunculated, papulonodules. They typically appear in late childhood and increase in number throughout adolescence and adulthood; nearly all adults with NF1 have at least a few. In some cases, hundreds of these lesions are present, causing considerable disfigurement.
PLEXIFORM NEUROFIBROMAS Plexiform neurofibromas occur in approximately 30% of patients with NF1 and appear clinically as extensive soft subcutaneous swellings with indistinct margins. Hyperpigmentation or hypertrichosis of the overlying skin is common, as is hypertrophy of underlying soft tissue and bone (regional gigantism).
Plexiform neurofibromas develop earlier than do nodular lesions, frequently becoming evident in infancy or childhood, and may cause severe disfigurement and functional impairment. Approximately 10% of plexiform neurofibromas involve the face, commonly the upper eyelid and orbit (Fig 28-3). The greater involvement of the upper eyelid’s temporal portion gives the eyelid margin an S-shaped configuration. Complete ptosis may result from the increasing bulk and weight of the upper eyelid. Glaucoma in the ipsilateral eye is found in as many as half of cases.
Complete excision of an eyelid plexiform neurofibroma is generally not possible. Treatment is directed toward the relief of specific symptoms. Surgical debulking and frontalis suspension procedures can reduce ptosis sufficiently to permit binocular vision. Clinical trials examining use of biologic agents in the treatment of these lesions are under way.
Jakacki RI, Dombi E, Potter DM, et al. Phase 1 trial of pegylated interferon-α-2b in young patients with plexiform neurofibromas. Neurology. 2011;76(3):265–272.
OPTIC PATHWAY GLIOMA This low-grade pilocytic astrocytoma (optic glioma) involves the optic nerve, chiasm, or both and is among the most characteristic and potentially serious complications of NF1. Optic pathway gliomas are present in approximately 15% of patients and are symptomatic (ie, produce significant vision loss, proptosis, or other complications) in 1%–5%.
Magnetic resonance imaging (MRI) is the preferred technique for diagnosis. The orbital portion of an involved optic nerve usually shows cylindrical or fusiform enlargement (Fig 28-4), often with exaggerated sinuousness or kinking, creating an appearance of discontinuity or localized constriction on axial images.
Optic gliomas that become symptomatic in patients with NF1 nearly always do so before age 10 years, often following a brief period of rapid enlargement. Even without treatment, some gliomas enter a phase of stability or slower growth, and spontaneous improvement has been documented in a few cases.
Tumors confined to the optic nerve at the time of clinical presentation infrequently extend into the chiasm. Chemotherapy may be effective in halting their growth. Radiation therapy can be useful, especially in cases of sudden vision loss or rapid growth. However, the efficacy of these treatments is difficult to evaluate, even in large studies, because of the widely variable natural history of this disease. Subtotal orbital excision for relief of disfiguring proptosis in a blind eye can be considered.
In addition to causing bilateral vision loss, tumors involving primarily the chiasm may result in significant morbidity, including hydrocephalus and hypothalamic dysfunction. Chiasmal glioma in patients with NF1 carries a much better prognosis than in individuals without NF.
OTHER NEUROGLIAL ABNORMALITIES There are other, less common neuroglial abnormalities. Abnormal proliferation of peripheral neuroglial or other neural crest–derived cells may occur in deeper tissues and visceral organs as well as in skin (spinal and gastrointestinal neurofibromas, pheochromocytoma). Prominence of corneal nerves, thought to represent glial hypertrophy, may be observed on slit-lamp examination in as many as 20% of cases. In rare cases, a localized neurofibroma develops within the orbit. Retinal hamartomas that are indistinguishable from those seen in tuberous sclerosis have also been reported.
Other manifestations NF1 is associated with an increased (but still generally low) incidence of several conditions that cannot be explained by abnormal proliferation of neural crest–derived cells. These include various benign tumors that involve the skin or the eye (juvenile xanthogranuloma, retinal capillary hemangioma) and several forms of malignancy (leukemia, rhabdomyosarcoma, pheochromocytoma, Wilms tumor). Also relatively common are bony defects such as scoliosis, pseudarthrosis of the tibia, and hypoplasia of the sphenoid bone (which may cause ocular pulsation). Sphenoid dysplasia may be associated with neurofibromas in the ipsilateral superficial temporal fossa as well as in the deep orbit. Several ill-defined abnormalities of the CNS (macrocephaly, aqueductal stenosis, seizures, and developmental delay) are also seen with greater frequency in patients with NF1.
Diagnosis and monitoring NF1 is diagnosed by genetic testing or based on clinical findings when 2 or more of the following 7 criteria are met:
- six or more café-au-lait spots that are >5 mm in diameter in prepubescent children or >15 mm in diameter in postpubescent children
- two or more neurofibromas of any type or 1 plexiform neurofibroma
- freckling of axillary, inguinal, or other intertriginous areas
- optic pathway glioma
- two or more Lisch nodules of the iris
- a distinctive osseous lesion, such as sphenoid bone dysplasia or thinning of the long-bone cortex, with or without pseudarthrosis
- a first-degree relative with NF1, according to the above criteria
Lisch nodules may be used to confirm the presence of NF1 in a patient with café-au-lait spots. They may not be present in affected children, but the absence of such nodules in an adult makes the diagnosis unlikely. Some practitioners recommend neuroimaging to look for optic glioma in all children with NF. Others recommend routine examination and reserve the use of neuroimaging for patients who develop abnormalities of vision, pupil function, or optic disc appearance. An appropriate interval for periodic ophthalmic reassessment in childhood is 1–2 years, unless a specific abnormality requires closer observation.
Fisher MJ, Loguidice M, Gutmann DH, et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol. 2012;14(6):790–797. Epub 2012 Apr 3.
Kalamarides M, Acosta MT, Babovic-Vuksanovic D, et al. Neurofibromatosis 2011: a report of the Children’s Tumor Foundation annual meeting. Acta Neuropathol. 2012;123(3):369–380.
Neurofibromatosis 2 (NF2) is much less common than NF1; it has an incidence of 1:33,000–1:40,000. It is an autosomal dominant condition, and approximately half of all cases show sporadic mutation. The NF2 gene, neurofibromin 2 (merlin), is located on chromosome 22 (22q12.2) and encodes for a cytoskeletal membrane-linking protein. NF2 is diagnosed clinically by the presence of bilateral acoustic neuromas (eighth cranial nerve tumors) or by a first-degree relative with NF2 and presence of a unilateral acoustic neuroma, neurofibroma, meningioma, schwannoma, glioma, or early-onset posterior subcapsular cataract.
Patients with NF2 typically present in their teens or early adulthood with symptoms related to the eighth nerve tumor(s), including decreased hearing or tinnitus. Ocular findings may predate the onset of symptoms. Therefore, the alert ophthalmologist may be able to help identify the potential for CNS tumors before they become symptomatic. The most characteristic ocular finding in NF2 is lens opacity, especially posterior subcapsular cataract or wedge-shaped cortical cataracts. Up to 80% of patients have epiretinal membranes. Less common findings are retinal hamartoma and combined hamartomas of the retina and retinal pigment epithelium (RPE). Lisch nodules of the iris can occur in NF2 but are infrequent.
Tuberous sclerosis (TS), or Bourneville disease, has a reported incidence of approximately 1 in 10,000. Two distinct genes give rise to TS: TSC1 on 9q34 and TSC2 on 16p13.3. Their proteins, hamartin and tuberin, respectively, are tumor suppressors. Transmission as an autosomal dominant trait has been documented in numerous pedigrees, but new mutations account for as many as 80% of cases.
The 3 classic findings, known as the Vogt triad, are cognitive impairment, seizures, and facial angiofibromas, although all 3 are present in only about 30% of patients with TS. This disease is characterized by benign tumor growth in multiple organs, predominantly the skin, brain, heart, kidney, and eye. Clinical features are divided into major and minor features (Table 28-3). Two major or 1 major and 2 minor features are necessary for a definitive diagnosis.