a specific inhibitor of mitochondrial protein synthesis in patients with cystic fibrosis.791 Alcohol ingestion and intake of recreational and other drugs should be thoroughly reviewed in the clinical history. Maternal ingestion of alcohol and fetal alcohol syndrome may cause optic nerve hypoplasia or congenital optic atrophy.141,831 In adults, some cases of the socalled cases tobacco-alcohol amblyopia have been shown to represent variants of Leber hereditary optic neuropathy,178 and whether tobacco-alcohol amblyopia can develop in the absence of a genetic predisposition is uncertain.

Cecocentral scotomas are the typical visual field defects in toxic/nutritional optic neuropathies, but they may be difficult to elicit in the early stages of these disorders.

Neurodegenerative Disorders with Optic Atrophy

There are a large and ever-expanding number of neurodegenerative disorders of the central and/or peripheral nervous system that can be associated with ophthalmologic disorders, including optic atrophy (Table 4.4). The distinction between neurodegenerative disorders and other genetic and neurometabolic disorders is becoming increasingly blurred as the responsible gene, its enzyme and protein products, and the specific metabolic defect are identified. Many neurodegenerative disorders show considerable overlap, demonstrating combinations of progressive degeneration of the cerebellum, pyramidal tract, polyneuropathies (sensory neuropathy, motor neuropathy, or both), deafness, and optic atrophy. In some instances, overlapping features preclude separate nosologic classification. Generally, these disorders are diagnosed

on the basis of associated clinical findings and other features rather than by the optic atrophy. In some sense, even isolated optic atrophies, such as dominant optic atrophy, may be thought of as limited neurodegenerative disorders that preferentially involve the optic nerve.

Degenerative disorders affecting gray matter are less common than those affecting white matter, and generally the two are very difficult to differentiate on clinical grounds. Optic atrophy is common in children with neurodegenerative disease. Because it reflects irreversible injury to the pregeniculate pathways, optic atrophy occurs preferentially in neurodegenerative disorders that primarily affect the white matter. Children with white matter disease tend to present with corticospinal tract dysfunction, peripheral neuropathies, and optic atrophy. In contrast, gray matter disease tends to produce seizure disorders, movement disorders, and dementia. The child with purely gray matter disease (e.g., Tay– Sachs disease) will tend to have seizures without optic atrophy, whereas the child with purely white matter disease may present with optic atrophy without seizures. The development of optic atrophy in a child with seizures may signify a spread of the disease process from gray to white matter (as may occur in the later stages of Leigh disease). Although neurodegenerative and neurometabolic diseases are often classified as gray or white matter disorders, most eventually involve both gray and white matter to some degree. Neurodegenerative disorders that are commonly associated with optic atrophy are summarized in Table 4.4.

Some of the neurodegenerative disorders present in infancy as infantile progressive encephalopathies, and these are exemplified by the first six disorders subsequently discussed. These represent a heterogeneous group of disorders that can be differentiated on the basis of metabolic abnor-

Table 4.4  Neurodegenerative disorders commonly associated with optic atrophy in children

Pelizaeus–Merzbacher disease Canavan disease

X-linked adrenoleukodystrophy Alexander disease

Leigh disease

Metachromatic leukodystrophy Krabbe disease

Multiple sclerosis

Spinocerebellar degeneration (Friedreich ataxia, olivopontocerebellar degeneration)

Neuronal ceroid lipofuscinosis Hallervorden–Spatz disease MELAS

Congenital lactic acidosis Vanishing white matter disease

malities (e.g., Krabbe disease, Menke syndrome), typical histopathological findings (e.g., neuronal ceroid lipofuscinosis), additional extra-cerebral findings (e.g., Aicardi syndrome), or dysmorphic features (e.g., PEHO syndrome).

Krabbe’s Infantile Leukodystrophy

This is an autosomal recessive disorder of sphingolipid metabolism that is caused by mutations in the galactosylceramide gene on chromosome 14q31.44,918 Affected children are normal at birth, but begin to deteriorate within the first few months of life, developing irritability, restlessness, spasticity, convulsions, hyperacusis and, in the terminal stages, bulbar signs, deafness, and flaccidity. Optic atrophy and blindness are prominent features. MR imaging shows symmetrical white matter involvement with a predilection for the parietooccipital regions. Diagnosis is established by assay of galactocerebrosidase in leukocytes. Death usually occurs by the age of 2 years.905 Autopsy shows loss of myelin in the brain, with globoid cells in the area of demyelination. A rare, juvenile-onset form of Krabbe disease has also been reported in association with optic atrophy.44

Canavan Disease (Spongiform Leukodystrophy)

This is an autosomal recessive disorder in which patients who are often asymptomatic in their early months show a wide spectrum of clinical presentation that includes macrocephaly without hydrocephalus, poor head control, seizures, hypotonia, lack of movements, optic atrophy, and significant developmental delay.13 This disorder occurs almost exclusively in Ashkenazi Jews. MR imaging reveals diffuse symmetric lesions of the cerebral white matter and, in the later stages, cortical atrophy. Death usually occurs between the ages of 1 and 3 years. Histopathology reveals demyelination and spongy degeneration

in the cortex. The disease is caused by deficiency of aspartoacylase, the enzyme responsible for the hydrolysis of N-acetylaspartic acid into acetate and l-aspartate.13 Deficiency of aspartoacylase in skin fibroblasts or N-acetylaspartic acid in the urine is diagnostic of the disease.13 The abnormal gene is localized to the short arm of chromosome 17.66,304

Subacute Necrotizing Encephalomyelopathy

(Leigh Disease)

Leigh disease is a neurodegenerative syndrome that can result from multiple different biochemical defects that all

impair cerebral oxidative metabolism.64,150,200,206,589,704,761,798,885,890

Depending on the genetic defect, it may be inherited in an autosomal recessive, X-linked, or maternal pattern,573 and may present in an infantile, juvenile, and an adult form.468 It is caused by a deficiency of pyruvate carboxylase, with increased levels of lactate and pyruvate in the blood. The infantile form begins within the first 6 months of life. A positive family history is present in half of the infantile cases. In infants, the insidious course of the disease ranges from weeks to years, with patients developing somnolence, deafness, psychomotor regression, and spasticity, in addition to optic atrophy and blindness. Death occurs between 2 and 10 years of age. Autopsy findings show bilateral, multifocal, subacute necrotic lesions from the thalamus to the pons, and demyelination in the optic nerve. The clinical features of Leigh disease may be associated with several biochemical defects, which can arise from either nuclear or mitochondrial gene mutations.249

Childhood lactic acidosis comprises a number of clinically heterogeneous disorders that share increased levels of lactate and pyruvate in the blood.357 In addition to Leigh disease, disorders showing childhood lactic acidosis include MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), pyruvate decarboxylase deficiency, pyruvate dehydrogenase deficiency, pyruvate dehydrogenase phosphatase deficiency, cytochrome c oxidase deficiency, dietary ketoacidosis, or idiopathic.117,357 Optic atrophy is a common neuro-opthalmologic finding in children with lactic acidosis due to their propensity for CNS white matter involvement.357

Pelizaeus–Merzbacher Disease

(Sudanophilic Leukodystrophy)

This is an X-linked recessive disorder that differs from the other leukodystrophies by the presence of irregular pendular nystagmus and head shaking in the first few months of life. Poor head control, cerebellar dysfunction, choreiform movements of the arm, and spasticity develop later. The nystagmus may later disappear. Optic atrophy and retinal degeneration

occur later. Intellectual function is generally preserved despite neurological deterioration. Death ensues between 5 and 7 years of age. Autopsy findings show patchy demyelination.

PEHO Syndrome

PEHO syndrome denotes progressive encephalopathy, with edema, hypsarrhythmia, and optic atrophy. It is apparently transmitted as an autosomal recessive disorder, and most patients are of Finnish descent. Most patients are healthy or only slightly hypotonic at birth. The disorder becomes manifest at 2 weeks to 3 months of age, with progressive hypotonia, poor vision, and limb jerks. Affected patients also show infantile spasms, exaggerated deep tendon reflexes, and early arrest of psychomotor development. Subcutaneous edema in the limbs and blindness with optic atrophy and nystagmus are also present.812,813 Affected infants show typical dysmorphic facial features that include epicanthal folds, midfacial hypoplasia, promi-

nent ear lobes, gingival hypertrophy, small chin, and tapered fingers. The most typical physical finding is subcutaneous nonpitting edema of the limbs and face. A few patients have survived into the teens. MR imaging scans show cerebellar hypoplasia as the predominant finding.516 A progressive brain atrophy may involve the brain stem, cerebellum, and optic nerves, sometimes with abnormal myelination suggestive of periventricular leukomalacia. A metabolic defect has yet to be determined.573 One recent study found deficient production of IGF-1, which may permits elevated levels of nitrous oxide to damage the cerebellar granule cells, promote seizures, damage cerebellar granule cells, and permit the underlying neurodegeneration in PEHO syndrome.723

Neonatal Leukodystrophy

This is one of the peroxisomal disorders that includes a wide array of disorders including Zellweger cerebrohepatorenal