The earliest evidence of this condition is often a photosensitive dermatitis in the first few months of life, followed by growth retardation, bony abnormalities, and a characteristic facial appearance in the first few years. Progressive cerebellar dysfunction and motor deterioration ensue. The facies is distinctive, with sunken eyes and cheeks, decreased tearing and corneal scarring, miotic pupils, sharp nose, jutting chin, thin lips, inadequate salivation, and dental caries.258 Cataracts, pigmentary retinopathy, and optic atrophy contribute to the visual loss.117,145 ERG shows variable degrees of reduction of scotopic and photopic responses, which seem to parallel the fundus changes and the age of the patient.196

A CT shows calcifications in basal ganglia and dentate nucleus of the cerebellum along with cerebral atrophy.80 MR imaging demonstrates delayed myelination and T2 prolongation in periventricular white matter, basal ganglia, and dentate.80 The subcortical U fibers may be involved early, but more often they are preserved until later.17,74 Some children have been noted to have normal-pressure hydrocephalus and have benefitted from shunting.107

Neuropathologic changes resemble those of Pelizaeus– Merzbacher disease, showing patches of nonmyelination with preserved islands of normal myelin. In addition, globus pallidus and cerebellum may show calcifications. No biochemical abnormality has yet been identified for this syndrome, and diagnosis is made on clinical grounds.

Alexander Disease

Alexander disease is a leukodystrophy that usually presents in infancy with megalencephaly, dementia, spasticity, and seizures.7 However, it may also present in later childhood and, rarely, in adulthood,280,341 when its progression may be confused with multiple sclerosis.147 Characteristic pathologic findings include accumulation of Rosenthal fibers throughout the cerebral white matter, with striking demyelination and cavitation of the frontal lobes but relative sparing of the cerebellum.7,11,82,170,254 It has been postulated that Rosenthal fibers form as a consequence of a metabolic disturbance of astrocytes that in turn leads to the degradation of excessive amounts of glial filaments.87 Most cases have been shown to be due to mutations in the gene encoding glial fibrillary acidic (GFAP) protein.164

This sporadic neurodegenerative disorder occurs in an infantile and a juvenile form. The infantile form begins in the first year of life, with intellectual and motor retardation, spasticity, seizures, and progressive megalencephaly without hydrocephalus. The head enlargement is progressive, and hydrocephalus may be superimposed in later stages.107 The prominent neuro-ophthalmologic feature in the infantile form is optic atrophy. The juvenile form is rare and has

its onset between 7 and 14 years of age. Bulbar or pseudobulbar dysfunction occurs, including difficulty swallowing, abnormal speech, nystagmus, ptosis, facial diplegia, and atrophy of the tongue. Mentation appears to be normal.126 The possibility of an adult form has been suggested with a clinical picture resembling multiple sclerosis. On pathological examination of the brain, the characteristic finding is refractile cyanophilic bodies related to astrocytes around blood vessels. These occur throughout gray and white matter and in the optic nerves and tracts.270 Loss of myelin is marked in the infantile cases. The brainstem may be predominantly involved in the juvenile form.

Neuroimaging studies show abnormalities in the white matter beginning in the frontal areas and gradually proceeding posteriorly. CT scanning shows low-density lesions in the frontal lobes with contrast enhancement near the tips of the frontal horns.99 MR imaging shows a similar pattern of abnormality, with prolonged T1 and T2 relaxation times progressing from anterior to posterior white matter. Peripheral white matter is affected early.17,236

The clinical diagnosis of Alexander disease is not straightforward because there is no biochemical or genetic marker for this disease. Although mutations in the gene for GFAP have been suggested as a cause of infantile and juvenile variants of this disorder,31,40 other primary causes must be eliminated, and a final diagnosis is made by finding demyelination with an abundance of Rosenthal fibers on biopsy or at cerebral autopsy. There is also controversy surrounding whether Alexander disease represents a distinct nosologic entity. Its characteristic Rosenthal fibers are found around some intracranial cysts, in hemimegalencephaly, and in some astrocytic tumors. There is some evidence that they represent a reaction to metabolic stress and that they are not specific to any single disease entity. Nevertheless, they present more diffusely and in larger numbers in cases termed Alexander disease.146 There is no specific therapy for this condition.

Sjögren–Larsson Syndrome

Sjögren–Larsson syndrome is an autosomal-recessive neurocutaneous disorder with a prevalence of less than 0.4 per 100,000 population.351 Originally described in 1957 by Sjögren and Larsson, this white matter disease comprises the clinical triad of spastic diplegia or tetraplegia, mental retardation, and ichthyosis.288 It is caused by disturbed lipid metabolism due to a deficiency of the microsomal fatty aldehyde dehydrogenase (FALDH) enzyme, which catalyzes the oxidation of many different medium and long-chain fatty aldehydes into fatty acids. Therefore, FALDH deficiency results in the accumulation of fatty alcohols and fatty aldehydes in body tissues.113 In addition to their neurologic symptoms,