syndrome, infantile refsum disease, neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata, X-linked adrenoleukodystrophy, primary hyperoxaluria type I, and classical Refsum disease.265 The various clinical features of these disorders are summarized in Table 4.5. With the exception of X-linked adrenoleukodystrophy, the inheritance of these disorders is autosomal recessive. In patients suspected of harboring peroxisomal disorders, analysis of cultured fibroblasts for very long chain fatty acids (VLCFA), dihy- droxyacetone-phosphate acyltransferase (DHAPAT), and/or plasmalogen are helpful.

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is an autosomal recessive disorder that is usually caused by mutations in the arylsulfatase A (ARSA) gene on chromosome 22q13.31. Several forms of this autosomal recessive disorder are recognized, including a late infantile and a juvenile form. The late infantile form presents at between 1 and 2 years of life, with gait disorder and strabismus. Speech impairment, spasticity, intellectual deterioration, and optic atrophy follow. Optic atrophy is found in about one-third of cases and is, along with cortical visual impairment, a cause of significant visual loss.269 Other, less common, ophthalmological features include retinal arteriolar attenuation, course granular macular pigmentary deposition, rippling of the internal limiting membrane (due to retinal atrophy), and a cherry red spot. The ERG is usually normal or mildly abnormal, in contrast with the various juvenile amaurotic idiocies. Deep tendon reflexes are reduced or absent in the lower extremities. Patients may suffer unexplained episodes of fever or abdominal cramps. The CSF protein is elevated. Neuroimaging demonstrates white matter disturbances, especially of the periventricular region. The diagnosis was formerly made by demonstration of intracellular metachromatic substances in the urine and assay of arylsulfatase A in leukocytes. When the disease begins before 30 months of age, death usually ensues between 5 and 10 years of age.918 No treatment has been shown to be effective.

X-Linked Adrenoleukodystrophy

(Addison–Schilder Disease)

Adrenoleukodystrophy is an X-linked recessive disorder that is caused by mutations in the ATP-binding cassette gene (ABCD1) on chromosome Xq28.918 It usually presents with visual defects and neurological disturbances at an average age of 7 years. Affected boys may display signs of attention deficit disorder, behavioral disturbance, visual loss, incoordination, and dementia.918 These bizarre visual symptoms

and their associated behavioral disturbances may lead to the mistaken diagnosis of hysterical blindness, particularly in the early stages when the fundus findings are normal.847 Affected boys develop hormonal disturbances manifesting as Addison’s disease, with skin hyperpigmentation or hypogonadism.

The early visual impairment early is cortical in origin. Neuroimaging demonstrates symmetric bilateral involvement of the periventricular white matter, especially posteriorly (hence, the cortical visual impairment). Optic atrophy develops later in the disease. The diagnosis can be confirmed by finding an excess of very long chain fatty acids in cultured skin fibroblasts, white cells, red blood phospholipids, or total plasma lipids.592 Carrier females occasionally develop a variable degree of neurological impairment and may have symptoms and MR lesions similar to those found in multiple sclerosis. Genetic counseling is therefore important for symptomatic females. The disease is characterized by inexorable neurological deterioration culminating in death within a few years. Bone marrow transplantation has stabilized or improved neurologic function in selected cases.918

Pantothenate Kinase-Associated Neurodegeneration

Pantothenate kinase-associated neurodegeneration (formerly known as Hallervorden–Spatz syndrome) is a rare familial neurodegenerative disorder that presents in childhood or early adolescence with dystonia, parkinsonism, choreoathetosis, corticospinal tract involvement, optic atrophy, pigmentary retinopathy, and cognitive impairment.855 Dystonia is more frequent in early-onset patients, whereas parkinsonism is seen predominantly in adult-onset patients. It is also referred to as neurodegeneration with brain iron accumulation, with iron deposition in the globus pallidus producing the characteristic “eye-of-the-tiger” sign on MR imaging. Characteristic MR changes include decreased signal intensity in the globus pallidus and the substantia nigra on T2-weighted images compatible with iron deposition.29,837 Death occurs an average of 15 years after onset. There is no known biochemical basis or genetic marker for the disorder yet.8

Before the advent of MR imaging, confirmation of the diagnosis was done on autopsy.

A mild degree of visual impairment is frequently described in Hallervorden–Spatz syndrome, typically attributed to optic atrophy, pigmentary retinopathy, or tapetoretinal degeneration. Rarely, visual loss due to optic atrophy is the presenting symptom.135 However, one recent ophthalmologic study of 16 patients found no patient with optic atrophy.228 Mutations in the PANK2 gene on chromosome 20p12.3-p13 are associated with a younger age at onset and a higher frequency of dystonia, dysarthria, intellectual impairment, and gait disturbance.433,855