most patients suffer from photophobia and subnormal visual acuity. A crystalline maculopathy, in which crystalline dots are scattered throughout the perifovea within the inner retinal layers, develops in early childhood. These crystals should be specifically sought in the child who presents with icthyosis, as they are present whenever the enzyme deficiency is found. Optical coherence tomography (OCT) shows focal hyperreflectivities in the perifoveal ganglion cell and inner plexiform layers, together with a cystic foveal atrophy that is not visible ophthalmoscopically.113 MR imaging shows an arrest in myelination, signal abnormalities involving periventricular white matter, and mild ventricular enlargement.351

Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis is a rare autosomal lipid storage disease resulting from deficiency of the mitochondrial enzyme sterol 27-hydroxylase, resulting in a reduced production of cholic acid and particularly chenodeoxycholic acid, and leading to accumulation of cholestanol and cholesterol in many tissues.330 Cerebrotendinous xanthomatosis is an important form of neurodegeneration that should be suspected in children who have chronic diarrhea. These children have bilateral cataracts, which develop after the first few years of life, and are therefore not accompanied by nystagmus.73 Over time, these children suffer mental deterioration, pyramidal tract dysfunction, and cerebellar ataxia.330 They eventually develop a neurologic picture that resembles multiple sclerosis. Cerebral atrophy and deep cerebellar white matter lesions are found on MR imaging.32,155 In addition to developing bilateral cataracts, some patients show clinical signs of optic neuropathy.73 Chronic elevation of bile acids and cholestanol produce these neurologic abnormalities. It is critical to look for cataracts in the child with chronic diarrhea, because identification and treatment of this syndrome can prevent these neurologic complications. Early treatment with chenodeoxycholic acid stabilizes the condition.330

Peroxisomal Disorders

Peroxisomes are subcellular organelles that were first recognized in 1954 in the proximal tubule of the kidney. They are found in all eukaryotic species and in almost every cell. The name was chosen because these organelles produce and reduce hydrogen peroxide. They also contain enzymes needed for the oxidation of amino and dicarboxylic acids. In this process, H2O2 is formed and then detoxified by catalase, another peroxisomal enzyme.93,245 In 1973, Goldfischer129 discovered that peroxisomes were absent in liver and renal tubular

epithelial cells of patients with Zellweger syndrome. Various peroxisomal functions were found to be absent. A specific biomarker for screening patients was first identified in 1984,226 and the first gene defect was identified in 1992.285 Thus, the major clinical syndromes attributable to peroxisomal biogenesis disorders (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondrodysplasia punctata) were all described before the biochemical and molecular mechanisms of peroxisomal dysfunction were understood.296

Inherited diseases of peroxisomes are divided into the peroxisomal biogenesis disorders, in which a mutation in one or more of the 12 peroxisomal assembly genes (PEX genes) results in a virtual absence of peroxisomes and a generalized loss in all peroxisomal function (e.g., the cerebrohepatorenal [Zellweger] syndrome, the infantile form of Refsum disease, the neonatal form of ALD, the rhizomelic type of chondrodysplasia punctata, and hyper-pipecolic acidemia), and those in which only a single peroxisomal function is impaired (e.g., X-linked adrenoleukodystrophy [ALD], the adult form of Refsum disease, and pseudorhizomelic chondrodysplasia).110,296,342

Abnormal retinal pigmentation occurs in Zellweger syndrome, neonatal ALD, hyper-pipecolic acidemia, and infantile Refsum disease. These children may have abnormal ERGs early in the course of the disease. Optic disc pallor has been reported in Zellweger syndrome, neonatal ALD, and hyperpipecolic acidemia.48,250

MR imaging studies in children with peroxisomal disorders have shown the following general abnormalities: (1) neuronal migrational disturbances in combination with hypomyelination, dysmyelination, or demyelination; (2) symmetrical demyelination of the posterior limb of the internal capsule, cerebellar white matter, and brainstem tracts with a variable affection of the cerebral hemispheres; and (3) symmetrical demyelination – exhibiting two zones: the first starting in the occipital area and spreading outward and forward, and the second involving the brainstem tracts. Biochemical studies performed on blood and urine are used to screen for the perioxisomal biogenesis disorders.296 DNA testing is possible for all of the disorders but is more challenging for Zellweger syndrome, which can be associated with 12 different PBX genes.296

Current treatment is mainly supportive, consisting of treating seizures, providing hearing aids, treating ocular disorders, and addressing other developmental needs. However, some therapeutic interventions have been successful in these patients. A diet low in phytanic acid has been successful in the treatment of adult Refsum disease. Oral bile acid administration has improved hepatobiiloary function in some infants with Zellweger syndrome. Newer experimental therapies directed at peroxisomal proliferation hold promise for more directed therapy.212,344

Zellweger Syndrome

Zellweger hepatorenal syndrome is an autosomal recessive disease characterized by unique facies, failure to thrive, and visual impairment. The characteristic craniofacial features include a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large anterior fontanel.296 Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. There is absence of neonatal and deep tendon reflexes and little spontaneous movement.296 The eyes may demonstrate corneal clouding, cataracts, glaucoma, optic atrophy, and retinal anomalies, with extinguished ERG waveforms. Homozygotes also have characteristic lens abnormalities consisting of a dense cortex producing a cortical-nuclear interface that is visible at the slit lamp through a dilated pupil. Hittner et al153 have shown that the heterozygous parents of four infants with Zellweger syndrome had lens changes consisting of curvilinear condensations in the cortical region in the same location as the lens changes in the homozygous state. The liver is enlarged, and there are renal cysts. Bone stippling is seen at the patella and in other bones in about 50% of patients.296

Although most children die within the first year of life, a later-onset form is recognized in which there is some degree of psychomotor development, with development of head control, independent walking, and speech.296 These patients tend to have sensorineural hearing loss and retinitis pigmentosa, leading to the initial diagnosis of Usher syndrome or even Leber congenital amaurosis.296 The characteristic neuronal migration abnormalities are easily demonstrated by MR imaging.328 These include periventricular neuronal heterotopias, pachygyria, and polymicrogyria.347

In some children, a leukodystrophy develops, with degeneration of myelin in the CNS, loss of acquired skills, and development of spasticity.296 The gross pathologic abnormalities relate to neuronal migration abnormalities and polymicrogyri. Microscopically, there is evidence of gliosis and accumulation of lipids; however, unlike storage diseases, the lipid droplets in Zellweger syndrome are in the astrocytic cytoplasm rather than in macrophages.3 The severe lack of myelin noted histologically in the brains of these infants may be due to a combination of disturbed myelination and accelerated demyelination.4 The combination of neuronal and white matter disease is reflected in retinal ganglion cell abnormality and optic atrophy.

Zellweger syndrome is caused by mutations in the PXE complementation genes, with 12 genes known to cause variants of the condition.296 Defects in the PXE gene impair peroxisome assembly and multiple metabolic pathways confined to this organelle, providing the biochemical bases of the peroxisome biogenesis disorders.296 Zellweger cerebrohepatorenal syndrome is a severe form of diffuse peroxisomal deficiency.

Initially, the syndrome was attributed to the absence of or a decrease in the number of peroxisomes; however, peroxisomal membrane ghosts have now been identified in cells, indicating that Zellweger syndrome and other conditions like it may in fact be due to peroxisomal assembly abnormalities.274 Plasma levels of VLCFAs, pipecolic acid, phytanic acid, and bile acid intermediates are all elevated in this syndrome.

Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is an X-linked disorder with a wide spectrum of phenotypes, varying from the rapidly progressive, childhood-onset, predominantly cerebral form to the more slowly evolving subtypes characterized by adrenomyeloneuropathy or Addison disease.221 The common pathophysiological feature in all forms is the accumulation of C26:0 and C24:0 VLCFA in the CNS and other tissues owing to their impaired degradation as a consequence of perixosomal dysfunction.286 The gene for ALD has been mapped to Xq28.214 It encodes for a peroxisomal membrane component termed the ALD protein, which belongs to the class of adenosine triphosphate-binding cassette proteins.150 The deficiency of a single peroxisomal function in X-linked ALD differs from neonatal ALD, in which there is impairment of multiple peroxisomal functions, including deficiencies in very long chain fatty acid (VLCFA) oxidation by phytanic acid oxidase and plasmalogen synthesizing enzymes.277

X-linked ALD presents at an average age of 7 years. Initial manifestations include increased skin pigmentation, decreased school performance, and “dementia-type” changes in memory and emotional expression. Motor disturbances may be prominent, with a stiff-legged spastic gait. Visual disturbances are common and, occasionally, they occur early. Homonymous hemianopia,275 visual agnosia, decreased visual acuity, strabismus, selective reading dysfunction, and cerebral blindness have all been reported. Optic atrophy eventually develops.184,191,312,355 The childhood form may manifest with emotional lability and hyperactivity, leading to the diagnosis of attention-deficit hyperactivity disorder.105,224,299 Cognitive decline, poor school performance, and visual loss typically follow. Rarely, visual loss can be the presenting symptom of the disease. Other neurological deficits include hearing loss, progressive ataxia, and spastic quadriparesis. Children may have skin hyperpigmentation due to adrenal dysfunction and adrenal deficiency can be lethal. Hypoadrenalism,158 and hypogonadism105 may also complicate the clinical course.230 The disease is fatal if untreated.192

Infants with ALD (neonatal form) have severe hypotonia and seizures at birth, and later they exhibit growth and mental retardation. Other neurological features include macrocephaly, large fontanels, nystagmus, optic atrophy, pigmentary retinopathy, and abnormal vision and hearing. Most children die

before 5 years of age. A few have survived until age 10. Other phenotypes include the rapidly progressive childhood form, the adolescent form, and the adult cerebral forms (adrenomyelopathy, which presents as slowly progressive paraparesis in adults, and Addison disease without neurologic manifestations).223 These phenotypes are frequently misdiagnosed, respectively, as attention-deficit hyperactivity disorder, multiple sclerosis, or idiopathic Addison disease. About 50% of female carriers develop a spastic paraparesis secondary to myelopathic changes similar to adrenomyeloneuropathy, often leading to the misdiagnosis of multiple sclerosis.

The biochemical hallmark of ALD is excess VLCFA, which can be measured in cultured skin fibroblasts, white cells, red blood phospholipids, or total plasma lipids. The concentration of C26:0 is elevated to approximately five times normal. Assays of long chain fatty acids in plasma, cultured chorion villus cells and amniocytes, and mutation analysis permit presymptomatic and prenatal diagnosis, as well as carrier identification. The timely use of these assays is essential for genetic counseling and therapy. Early diagnosis and treatment can prevent overt Addison’s disease and significantly reduce the frequency of the severe childhood cerebral phenotype. A promising new method for mass newborn screening has been developed. When implemented, it should have a profound effect on the diagnosis and management of X-linked ALD. Studies of choroinic villus sampling or amniocentesis now permit accurate prenatal identification of affected male fetuses. The finding of normal cognitive function in neurologically and radiologically normal boys with X-linked adrenoleukodystrophy suggests that prevention and timely institution of therapy can potentially preserve cognitive function.71 The plasma VLCFA assay is the recommended diagnostic procedure in males.222 Plasma VLCFA levels are increased on the day of birth.

Electrophysiological findings in two cases of neonatal ALD were reported by Verma et al333 One child was examined at age 1 year and the other at age 3½ years. Neither child demonstrated visual following responses, and both had severe seizures and long-tract signs. Both had nonrecordable or extremely diminished ERG responses and no consistent, identifiable positivity in VEP responses except for the right eye of the 1-year-old child, which showed a delayed positive wave with a mean latency of 137 ms. Ophthalmological examination of the younger patient showed normal media, normally reactive pupils, full extraocular movements, intermittent fine jerk nystagmus on horizontal gaze, and unremarkable fundi other than mild temporal pallor in each eye. The older child had sluggishly reactive pupils, pendular nystagmus, clear media, bilateral optic atrophy, and retinitis pigmentosa, suggesting a degeneration of photoreceptors and an accumulation of lipids in the ganglion cells.

Battaglia et al24 have studied the EEG, ERG, and flash VEP in 14 boys with X-linked ALD and in two siblings of

affected boys. These siblings had adrenocortical deficiency but were neurologically normal. All 14 affected boys had EEG abnormalities characterized by irregular, large-amplitude, slow activity. Similar EEG findings were seen in the two siblings of affected patients. The ERG was normal in all cases. The VEP was abnormal in four of 12 cases. The recording deteriorated over a short time frame in two cases and was low or unrecordable when first measured in two others. The VEPs in two siblings were normal.24 Detection of the carrier state of X-linked ALD by VEP has been reported.217

Neuroimaging studies are normal prior to the onset of symptoms.71 X-linked ALD classically involves the occipital white matter bilaterally. Areas of active demyelination may show intense contrast enhancement at the periphery of the lesions. These lesions are usually symmetric and may affect the posterior occipital region most severely. White matter lesions in the occipital region also characteristically involve the splenium of the corpus callosum early on. Occipital U fibers are relatively spared (Fig. 10.11). With time, the lesions extend forward to involve the lateral and medial geniculate bodies, the thalamus, and posterior limb of the internal capsule bilaterally. Cerebellar and brainstem white matter are relatively spared. Lesions are usually symmetric and may affect the posterior occipital region most severely, with the anterioroccipitalregionaffectedtoalesserextent.328 Pathologically disordered neuronal migration, including pachygyria and polymicrogyria, is the most striking abnormality.342

Fig. 10.11  Adrenoleukodystrophy. This T2-weighted MR image shows symmetrical hyperintense hemispheric lesions primarily involving occipital white matter (arrow)