10 Neurodegenerative Conditions of Ophthalmic Importance Mark S. Borchert and Sarah Ying he pediatric ophthalmologist is frequently asked to evaluate Tchildren with multiple neurological impairments for oph- thalmic manifestations of heritable neurological diseases. Occa- sionally these are diseases with specific ocular findings such as Kayser–Fleischer rings in Wilson’s disease or cherry-red spots in Tay–Sachs disease. More typically, they are diseases with non- specific findings such as optic atrophy or nystagmus. Such find- ings can be used to help direct the neurological workup. Less commonly, these children present to the ophthalmologist with ocular complaints primarily. The ophthalmologist must recog- nize those signs and symptoms that may be associated with neu- rodegenerative conditions and institute an appropriate workup. Although all these conditions are rare, a general ophthalmologist is likely to encounter several of them in their career. Most of the neurodegenerative conditions are metabolic and represent dysfunction of specific enzymes or enzyme systems. Many of these enzyme systems are associated with particular cellular organelles, allowing for the classification of these dis- eases according to the organelle that is disrupted. Examples of these are the lysosomal storage diseases, the mitochondrial dis- orders, and the peroxisomal diseases. Other neurodegenerative diseases have characteristic clinical and pathological findings without known enzyme defects. Clinically, these diseases each have their own stereotypical time and mode of onset, which allows for easy division of the neurodegenerative conditions into groups that present in infancy, early childhood, or late childhood (Tables 10-1 through 10-3). 324 chapter 10: neurodegenerative conditions 325 LYSOSOMAL STORAGE DISEASES AND LEUKODYSTROPHIES The lysosomal storage diseases are caused by dysfunction of lysosomal enzymes involved in the catabolism of complex lipids and sugars normally present in tissues, resulting in accumula- tion of intracellular storage products. Substances that may accumulate in nerve cell bodies and ultimately cause neuronal degeneration include sphingolipids, mucopolysaccharides, mucolipids, and oligosaccharides.81 When the catabolic defect affects primarily myelin con- stituents, it results in white matter fibrosis known as leukody- strophy. The leukodystrophies typically have visual loss as a primary manifestation of the disease. Those that are caused by lysosomal enzyme defects include metachromatic leukody- strophy and globoid cell leukodystrophy (Krabbe’s disease). Adrenoleukodystrophy is now recognized to result from defects of peroxisomal function. Spongiform leukodystrophy (Canavan disease) and sudanophilic leukodystrophy (Pelizaeus–Merzbacher disease) are disorders of myelin production. The metabolic defect in other leukodystrophies remains obscure. Other lysosomal dis- eases with ophthalmic manifestations, including secondary visual loss, are covered elsewhere. Krabbe’s Disease Krabbe’s disease (globoid cell leukodystrophy, galactosylce- ramide lipidosis) is an autosomal recessive condition character- ized by the accumulation of periodic acid–Schiff- (PAS-) positive material within microglial cells in the brain imparting a typical “globoid cell” appearance histologically. It is caused by a defi- ciency of the lysosomal enzyme galactocebroside ␤-galactosidase (galactocerebrosidase), which is encoded on chromosome 14. The accumulation of galactocerebroside results in central nervous system and peripheral nervous system demyelination. Typical infantile-onset Krabbe’s disease presents at age 4 to 5 months with irritability and muscular hypertonicity. Loss of vision or failure to develop vision is noted soon thereafter, as are recurrent low-grade fevers. Spasticity and opisthotonos rapidly supervene. Death usually occurs by age 2 years.186 The principal ophthalmoscopic finding is primary optic atrophy. Rarely, macular cherry red spots are seen.115 326 TABLE 10-1. Neurodegenerative Conditions with Onset in Infancy. Defective organelle Condition Principal ophthalmic manifestation Principal systemic manifestations Biochemical defect Lysosome GM1 gangliosidoses Cherry-red spots, nystagmus, Hypotonia, seizures, dysmorphism, GM1 ␤-galactosidase sphingolipidoses corneal opacities organomegaly neuro-ophthalmology handbook ofpediatric GM2 gangliosidoses Tay–Sachs disease Cherry-red spots, optic atrophy, Abnormal startle reflex, hypotonia, Hexosaminidase A nystagmus seizures Sandhoff disease Cherry-red spots, optic atrophy, Abnormal startle reflex, hypotonia, Hexosaminidase A and B nystagmus seizures, organomegaly Krabbe disease Optic atrophy, cortical blindness Irritability, spasticity, fevers Galactocerebrosidase Gaucher disease type 2 Esotropia, ocular motor apraxia Irritability, spasticity, seizures, Glucocerebrosidase organomegaly Niemann–Pick disease Cherry-red spots, optic atrophy, Organomegaly, hypertonia, loss of Sphingomyelinase type IA (formerly nystagmus motor skills, seizures, failure to type A) thrive Sialolipidosis (formerly Corneal clouding, pigmentary Psychomotor retardation Ganglioside sialidase mucolipidosis IV) retinopathy (presumed) Lysosome Mannosidosis type 1 Spokelike cataracts, corneal Coarse facies, severe psychomotor ␣-Mannosidase oligosaccharidoses opacities retardation, recurrent infections, organomegaly Lysosome Mucolipidosis II Corneal cloudiness Psychomotor retardation, coarse UPD-acetylglucosamine: mucolipidoses (I-cell disease) facies, kyphoscoliosis, lysosomal enzyme hyperplastic gingiva, N-acetylglucosaminyl- macroglossia, cardiomegaly 1-phosphotransferase Lysosome Infantile NCL Pigmentary retinopathy, optic Psychomotor delay, Palmitoyl protein ceroidoses (Santavouri–Haltia) atrophy choreoathetosis, seizures thioesterase (PPT) chapter Peroxisome Neonatal Pigmentary retinopathy, flat ERG Hypotonia, seizures, adrenal Multiple proteins of adrenoleukodystrophy insufficiency peroxisome biogenesis (PEX family) 10 Infantile Refsum’s Pigmentary retinopathy Dysmorphism, deafness, Multiple proteins of : conditions neurodegenerative disease organomegaly peroxisome biogenesis (PEX family) Zellweger syndrome Pigmentary retinopathy, optic High forehead, hypotonia, seizures, Multiple proteins of atrophy, corneal clouding, psychomotor retardation, perixosome biogenesis cataract, glaucoma hepatomegaly, polycystic kidneys (PEX family) Mitochondria Leigh syndrome Nystagmus, optic atrophy, Hypotonia, seizures, psychomotor Multiple ophthalmoplegia retardation None Canavan’s disease Optic atrophy, nystagmus Hypotonia, seizures, enlarged head Aspartoacylase Pelizaeus–Merzbacher Nystagmus, optic atrophy Spasticity, psychomotor retardation Lipophilin disease Unknown Lowe syndrome Cataracts, glaucoma Hypotonia, mental retardation, Inositol polyphosphate-5- rickets, renal failure phosphatase 327 TABLE 10-2. Neurodegenerative Conditions with Onset in Late Infancy or Early Childhood. 328 Defective organelle Condition Principal ophthalmic Principal systemic manifestations Biochemical defect manifestation Lysosome Metachromatic Optic atrophy, nystagmus Weakness, ataxia, dementia Arylsulfatase A sphingolipidoses leukodystrophy Gaucher disease type 3 Abducens palsy, ocular Dysphagia, spasticity, dementia, Glucocerebrosidase motor apraxia myoclonus organomegaly, neuro-ophthalmology handbook ofpediatric osseous lesions Niemannn–Pick type IS Pigmentary maculopathy Organomegaly, mental retardation Sphingomyelinase (formerly type B) Niemann–Pick type IIS Vertical gaze palsy Organomegaly, psychomotor NPC1 or HE1/NPC2 (formerly type C) retardation product Lysosome Aspartylglycosaminuia Crystalline cataracts Coarse facies, mental retardation, Aspartylglycosaminadase oligosaccharidoses diarrhea, recurrent infections Fucosidosis Tortuous conjunctival Coarse facies, psychomotor ␣-L-Fucosidase vessels deterioration, dysostosis multiplex, angiokeratoma Mannosidosis type II Spokelike cataracts, Coarse facies, psychomotor ␣-Mannosidase corneal opacities deterioration, dysostosis, multiplex, deafness, recurrent infections Schindler’s neuroaxonal Optic atrophy, nystagmus Weakness, peripheral neuropathy, ␣-N- dystrophy psychomotor retardation Acetylogalactosaminidase Lysosome mucolipidoses Mucolipidosis III Corneal clouding, Dysostosis multiplex, mental UPD-N-Acetylglucosamine: (pseudo–Hurler pigmentary retinopathy, retardation, coarse facies (mild) lysosomal enzyme N- polydystrophy) hyperoptic astigmatism acetylglu-cosaminyl-1- phosphotransferase Lysosome MPS 1H (Hurler) Corneal clouding, Dysostosis multiplex, ␣-L-Iduronidase mucopolysaccharidoses pigmentary retinopathy organomegaly, coarse facies, mental retardation MPS II (Hunter) Pigmentary retinopathy, Dysostosis multiplex, Iduronate sulfatase corneal clouding (rare) organomegaly coarse facies, psychomotor retardation MPS III (Sanfilippo) Pigmentary retinopathy Severe mental retardation, mild Heparan N-sulfatase (MPS dysostosis multiplex, deafness IIIA) ␣-L- Acetylglucosaminidase (MPS IIIB) Acetyl-Co-A:␣- glucosaminide chapter acetyltransferase (MPS IIIC) N-Acetylglucosamine 6- sulfatase (MPS IIID) 10 : conditions neurodegenerative Lysosome ceroidoses Late infantile NCL Pigmentary retinopathy, Seizures, ataxia, spasticity, loss of Pepstatin-insensitive (Jansky–Bielschowsky) optic atrophy speech lysosomal peptidase Mitochondria MELAS syndrome Hemianopsia, cortical Seizures, lactic acidosis, Mitochondrial tRNAleu visual loss hemiparesis Peroxisome Adrenoleukodystrophy Cortical blindness, optic Quadriparesis,