months of age and appeared to have normal vision in early childhood. He went to the Head Start Program at age 4 and did well, by the parent’s account. At age 5, the child complained of everything being out of focus. His school performance declined, and he had difficulties with coordination. Over the next year, he developed staring spells and tremors. He was first seen by us at age 11. At that time, his IQ measured 64. His visual acuity was 20/20 in each eye, but the fundus examination showed a pigmentary maculopathy. The neurological examination was remarkable for hyperreflexia and difficulties with tests of coordination. The ERG was unrecordable under either scotopic or photopic conditions. The metabolic screen (including very long-chain fatty acids [VLCFA]) for storage diseases was negative; however, electron microscopy of white blood cells showed irregularly shaped, variably sized, dense, osmiophilic granular bodies. Tubular inclusions were commonly seen in several mononuclear cells.

Electrophysiological testing may facilitate the early diagnosis of Batten disease, and ERG typically demonstrates an electronegative waveform under both scotopic and photopic conditions. The most suggestive ERG feature of Batten disease is a markedly reduced b:a ratio in the single flash photopic ERG, with additional a-wave delay. An electronegative maximal response is consistent with the inner retinal localization of the gene product for CLN3.66 However, the diagnosis of Batten disease is now confirmed by molecular analysis of the CLN3 gene, with most disease alleles having the common 1.02 kb deletion.65 CLN3, on chromosome 16p- 11-12, encodes battinin, a 438 amino acid residue protein.

Neuropathologically, JNCL is associated with widespread neuronal degeneration, including retinal atrophy and massive loss of brain substance, and accumulation of intracellular lipopigments.38 Despite the abnormal electroretinogram, it has recently been proposed that the primary site of neural injury may involve the lateral geniculate nucleus with retrograde degeneration.38 Retinal degeneration may be caused by an accumulation of storage material in the ganglion cell layer, which may represent a primary microglial defect,252 or an upstream insult to the lateral geniculate nucleus producing primary optic atrophy and a retrograde retinal degeneration.345 It is unknown whether the associated reactive gliosis precedes or is triggered by neuronal loss.38

Brain biopsy shows enlargement of most neurons, with eccentric nuclei and peripheral displacement of the Nissl substance. The neuronal cytoplasm is filled with granular material that stains pale gray with Sudan black, orange with oil red O, and intensely red or purple with PAS. The neuronal granular material shows a bright yellow autofluorescence. With hematoxylin and eosin, the granules stain pale yellow, resembling lipofuscin. Electron microscopy (EM) of the tissue examined has shown these granules to be cytosomes with curvilinear profiles (Fig. 10.3).25,208 Before genetic testing was available, demonstration of these characteristic findings

Fig. 10.3  Electron microscopy of neuron demonstrating characteristic “fingerprint” profile. Courtesy of Gerald A. Fishman, M.D.

on electron microscopy was the standard confirmation of diagnosis in all forms of this disease. Tissue for examination was generally obtained via biopsy of conjunctiva, rectum, skin, or muscle.47,162,163 In some cases, the diagnosis can be established by examining the white blood cell buffy coat and finding: (1) vacuolated lymphocytes or azurophilic hypergranulated neutrophils on light microscopy, or (2) mem- brane-bound intracellular inclusions and fingerprint profiles on electron microscopy.162,208 An animal model with ultrastructural similarities to NCL may improve our molecular understanding of this condition.44

Lysosomal Diseases

Gangliosidoses

The sphingolipidoses, mucopolysaccharidosis, mucolipidoses, glycogen storage diseases, glycoproteinoses, and other storage diseases are the result of an abnormal accumulation of metabolic products within lysosomes. This accumulation is due to a relative deficiency in the activity of hydrolytic enzymes that may be absent or mutated to less effective forms or lacking in activator proteins.306

As with most other degenerative diseases, the categorization of the gangliosidosis by eponym has been replaced by a system based on biochemistry. The gangliosides are classified by the system of Svennerholm, in which the letter G refers to ganglioside, the number of sialic groups are referred to by M (mono), D (di), or T (trisials), and the number of hexosides

in the molecule is given by the subscript 1, 2, or 3 (tetrahexose sides are 1, trihexoside 2, and dihexosides 3).304 These biochemical categories are then further divided on the basis of age of onset and clinical features. GM2 gangliosides have the most prominent visual system involvement, with rare cases of GM1 reported with a cherry red spot.95

GM2 Type I (Tay–Sachs Disease)

Tay–Sachs disease, which is the most common of the gangliosidosis, constitutes over 90% of cases of GM2 gangliosidoses and remains the prototype of the neuronal lysosomal lipid storage disorders. This autosomal recessively inherited deficiency of hexosaminidase A causes accumulation of GM2 ganglioside in the neurons of the central nervous system (CNS) and retinal ganglion cells. In the gangliosidoses, ophthalmoscopy typically shows a macular cherry red spot (Fig. 10.4) that results from the accumulation of opaque gangliosides in the retinal ganglion cell layer surrounding the fovea, causing the retina to become turbid with a milky white discoloration and the normal choroidal circulation to be visible through the ganglion cell-free fovea.62 Other neurodegenerative diseases associated with a cherry red macula are summarized in Table 10.4.

The onset is in the first few months of life, with blindness, seizures, spasticity, and an exaggerated acoustic response (i.e., a startle response to sound) in the first year of life. The cherry red macula sign may disappear as retinal ganglion cells are lost.70,183,232,241 ERG remains normal throughout the course of the disease.241 A variety of ocular motor disturbances have been described.168 Horizontal conjugate gaze deviations and horizontal strabismus are early features.

As the disease progresses, there is sequential loss of voluntary movements, pursuit and optokinetic responses, voluntary saccades, random short saccades, and vestibularly elicited eye movements. Tonic downward ocular deviation may be a persistent sign late in the disease.168 The diagnosis is usually made by finding low levels of hexaminidase A. Over 100 heterogenous mutations have been found to cause this condition, with the beta-hexaminidase a subunit mRNA often unstable or absent.342 There is no definitive treatment, and death usually occurs by age 4.171

A late-onset variant of Tay–Sachs disease, due to a partial defect of hexosaminidase A, usually presents in adulthood

Table 10.4.  Pediatric neurodegenerative disorders associated with cherry-red macula*

but may also present in childhood.268 This form is more common in Ashkenazi Jews, and is characterized by a progressive course and variable clinical picture that includes ataxia, signs suggestive of motoneuron disease, and psychiatric symptoms.193 Affected patients do not develop cherry red spots but display a prominent and unique ocular motility disorder.268 Horizontal and vertical saccades may appear interrupted, stuttering, and multistep,268 and large saccades can stall in mid-flight, producing transient decelerations.193 CT scanning shows hyperdense areas in the thalamus, with white matter attenuation, a small cerebellum and brainstem, and ventricular dilation.343 Pathological examination of the brain reveals degeneration of cerebral white matter and atrophy of cerebellar hemispheres on gross examination. Neurons are distorted and ballooned and nuclei are displaced to the periphery of the cell. Glial cells are filled with large globules of glycolipid.306 Adult Tay–Sachs disease is associated with a distinct Gly-Ser mutation or seen in a compound heterozygote with the infantile Tay–Sachs mutation.342

GM2 ganglioside accumulates in large amounts in the CNS of patients with Tay–Sachs disease due to a failure of the deficient enzyme hexosaminidase A to cleave N-acetyl-hexosamine from accumulative molecule, thus blocking the normal metabolism of this lipid. The abnormal gene in Tay–Sachs disease is located on chromosome 15 and codes for the a chain of the enzyme.12

The diagnosis may be suspected on clinical grounds and is confirmed by assaying for the enzymatic activity of hexosaminidase A in leukocytes. Carrier screening and prenatal diagnosis of Tay–Sachs disease has been available for many years, and an analysis of the impact of the screening since 1974 indicates that the instances of laboratory error are extremely low. The identification of couples and pregnancies at risk has resulted in a dramatic decrease in the incidence of Tay–Sachs disease in the Jewish population.172

GM2 Type II (Sandhoff Disease)

This condition has similar neuro-ophthalmologic findings to Tay–Sachs disease but differs by virtue of its involvement of visceral tissues. Hexosaminidase A and B activity are both abnormal. Affected children develop hepatosplenomegaly, renal abnormalities, and cardiomyopathy.35 Death occurs by 2–4 years of age. Biochemical detection of the enzymatic abnormality can be performed on fibroblasts or leukocytes.198

GM2 Type III

These patients experience loss of vision later than those with GM2 types I and II. Ataxia develops between 2 and 6 years of age. Eye movement abnormalities, including pursuit deficit

and saccadic dysmetria, may be seen. Optic demyelination and atrophy are invariable, but rods, cones, and pigment epithelium remain unaffected. In GM2 type III, the ERG is normal, and the VEP is reduced or unrecordable.124,157 The normal ERG is important in distinguishing this type of gangliosidosis from NCL, which is associated with a severely reduced ERG.

Niemann–Pick Disease

Niemann–Pick disease includes three disorders. The first two (Niemann–Pick disease A and B [NPA and NPB]) are caused by acid sphingomyelinase deficiency with secondary accumulation of sphingomyelin. Niemann–Pick disease, type C (NPC), which is a lipid-trafficking disorder, was grouped with NPA and NPB in 1961, before the molecular bases of these disorders were understood. NPC is now known to be identical with disorders previously designated as Niemann– Pick disease types D, E and F.

In NPA, sphingomyelin accumulation occurs in both neural and visceral tissue, whereas type B has been characterized as causing visceral accumulation only. Patients with type A disease have a rapidly degenerative neurological course, usually leading to death before 4 years of age. The predominant ophthalmological feature is a classic cherry red spot in the retina.

NPB is primarily nonneurologic, and patients with type B disease generally live longer than those with type A. However, patients with type B develop massive hepatosplenomegaly, bony changes, and diffuse pulmonary infiltration. These children develop a characteristic macular halo consisting of a discreet, white, crystalline-appearing ring surrounding the fovea of each eye.58 This halo masks macular circulation on fluorescein angiography. It was believed that patients with NPB did not develop cherry red spots at the macula, but a recent natural history study has found that this lesion is relatively common in NPB.211

Patients with NPC are not sphingomyelinase-deficient but have variable sphingomyelin accumulation. An isolate in patients of Nova Scotian descent was previously named Niemann–Pick disease type D but is now known to be allelic with NPC. Type C disease has also been termed juvenile dystonic lipidosis, the Neville–Lake syndrome and the DAF (downgaze palsy, ataxia– athetosis, and foamy macrophages) syndrome.61 This condition may present at any age from fetal life to adulthood.

Neonatal presentations are dominated by visceral disease, and affected infants often succumb to liver or ventilatory failure. Later onset disease is characterized by an insidious neurologic deterioration characterized by progressive ataxia, dysphagia, dysarthria, dystonia and, eventually, dementia. Adult cases my masquerade as psychiatric diseases before the cerebellar and brainstem signs become prominent. Cataplexy occurs in about one quarter of patients, and sei-

zures in about one half. Hepatosplenomegaly may also be present, but its absence does not rule out the diagnosis. Neuro-ophthalmological findings figure prominently in this disease and serve as a biosurrogate to monitor disease progression. Saccades are slower and smaller and occur with larger latencies. As a rule, vertical movements are more severely affected than horizontal movements and downgaze is more affected than upgaze.61,267,290

Many patients display loss of vertical saccades, impaired downgaze, and loss of the fast phase of optokinetic nystagmus (especially downward) in the presence of preserved doll’s eye movements. Diagonal saccades may show a curved trajectory, and a horizontal component may contaminate attempted vertical eye movements. As with other supranuclear neurodegenerative disorders, prominent blinking may occur when attempting to make saccades. Over time, horizontal saccadic abnormalities may ensue, with the development of head thrusts to compensate for the eye movement abnormality.235 Smooth pursuit movements remain fairly well-preserved.108

The biochemical abnormality in type C disease is abnormal trafficking of lipids in the endosomal–lysosomal system. This leads to the accumulation of unesterified cholesterol, particularly in peripheral tissues, and glycosphingolipids (glucosylceramide, GM1 and GM2 gangliosides), most markedly in the CNS. The diagnosis is made by demonstrating accumulation of free cholesterol in cultured fibroblasts using filipin staining; the secondary defect in cholesterol re-esterification in the ER that is catalyzed by ACAT can also be measured but is less reliable. This biochemical defect is caused by mutations in two distinct genes: NPC1, located on chromosome 18, and NPC 2 on chromosome 14. Ninety-five percent of cases of NPC are associated with mutations in NPC1. More than 250 mutations have been described in NPC1.

A trial of cholesterol-lowering agents was ineffective in altering the clinical course of NPC242; more recently, a strategy aimed at reducing the accumulation of glycosphingolipids showed evidence of a modest benefit in stabilizing the disease.244 The primary endpoint of this study was the change in horizontal saccadic eye movement velocity.

Gaucher Disease

Gaucher disease is the most common lysosomal storage disease.243 Gaucher disease is an autosomal recessive disorder associated with reduced activity of the lysosomal hydrolase glucocerebrosidase, which is encoded by an extensively characterized gene located in chromosome 1q21.193,243 All three clinically determined types of Gaucher disease have a defect in the catabolic enzyme glucocerebrosidase, resulting in excessive accumulation of a glycolipid glucocerebroside within macrophages in multiple organs.2 The characteristic

lysosomal accumulation of storage material can be appreciated in the form of “Gaucher” cells in most tissues.

Diagnosis is usually established by assay of B-glucocere­ brosidase activity in peripheral leukocytes or skin fibroblasts.55 Type I is the most common type of Gaucher disease. It was originally termed nonneuronopathic because the brain and spinal cord are not primarily affected. More recent studies have shown an association of glucocerebrosidase mutations with parkinsonianism, and neuropathological changes in clinically type I Gaucher disease. Findings include hepatosplenomegaly, easy bruising, bone pain, fractures, and arthritis. It may present at any time from childhood to adulthood and may cause a pigmented bulbar conjunctival lesion, bringing the patient to ophthalmological attention.

Affected infants may show a supranuclear horizontal and vertical saccadic palsy that is usually distinguishable from congenital ocular motor apraxia in that it is not present at birth and vertical saccades are also affected.61,132,338 Some may show a macular or perimacular atrophy of the retina.46 Clusters of foamy macrophages in the retina may form scattered discrete white spots in the posterior pole, especially along the inferior vascular arcades.59,117 Enzyme replacement therapy is proven to be safe and effective in the treatment of type 1 Gaucher disease,120 producing amelioration of hepatosplenomegaly and of hematologic manifestations within 6–12 months.120,225 However, bone disease improves more slowly, and neurologic complications do not reverse with this treatment.120

Types 2 and 3 are known as neuronopathic forms because they affect the CNS. The locus for both disorders maps to 1q21.300 Type 2 is the acute neuronopathic infantile form, which is characterized by ocular motor apraxia, strabismus, trismus, opisthotonus, and death typically by 2 years of age. Patients are usually normal at birth but develop hepatosplenomegaly, developmental regression, and growth arrest within a few months.300 A “fixed” esotropia and a supranuclear horizontal gaze palsy are frequently seen.104 The finding of fixed esotropia in a child with hepatosplenomegaly should therefore be considered a dire prognostic sign of type 2 Gaucher disease. Some patients develop a cherry red spot and optic atrophy.300,311 Because enzyme replacement therapy is expensive and does not ameliorate the neurologic symptoms,120,215,225 treatment is rarely given.

Type 3 is the subacute juvenile neuronopathic form of Gaucher disease. It also affects the nervous system but tends to progress more slowly than type 2. It begins in the first decade with organomegaly and growth retardation, progressing to intellectual deterioration and seizures, sometimes characterized as a myoclonic dementia. Cranial nerve dysfunction and an isolated horizontal supranuclear gaze palsy may develop. Ocular motor involvement may range from isolated horizontal supranuclear gaze palsy to complete inability to generate voluntary or reflexive saccadic eye movements with substitution of compensatory blinks and head thrusts.243 Affected patients may display a selective