Neuro-Ophthalmic Manifestations

Sialidosis (Neuraminidase Deficiency) Types I and II: Neuro-ophthalmic Manifestations

J. Stanwood Till, M.D., E. S. Roach, M.D., and Barbara K. Burton, M.D.

The clinical details and ophthalmologic findings of two Neuraminidase deficiency, or sialidosis, is an siblings with neuraminidase deficiency (sialidosis) are autosomal recessive deficiency of the enzyme presented. One patient is best classified as having siali alpha-N-acetylneuraminic acid hydrolase (1). The dosis type 1, while the younger sibling has features of type II. Both exhibited classic cherry-red macular abnor term sialidosis was first suggested by Durand et malities, and the patient who would permit complete aI. (2) for patients with marked accumulation of ophthalmologic examination had both corneal and len sialic acid glycoconjugates in the urine and body ticular opacities. Markedly reduced neuraminidase ac tissues. On the basis of age of onset and other tivity was demonstrated in both patients. These two pa clinical features, the disorder has been divided tients, and 48 others from the literature, were reviewed to determine the frequency of various ophthalmologic into subtypes I and II (1). Type I was previously abnormalities with sialidosis. Macular cherry-red spots referred to as the cherry-red spot-myoclonus were present in all adequately described type I patients syndrome. Type II sialidosis has been further sub and all but three patients with type II disease. Visual divided into juvenile and infantile categories. field defects, diminished acuity, and optic atrophy, Type I sialidosis often presents with myoclonus in though less well documented, occurred in the majority of both type I and type II patients. Lenticular lesions adolescence and is rarely associated with mental were present in all but two of the 18 patients with de retardation, dysmorphic features, visceromegaly, tailed ocular examination, whereas corneal opacities or hearing loss. Juvenile type II sialidosis tends to were found more often in type II than type I disease. have a somewhat earlier age of onset and is more Key Words: Sialidosis-Neuraminidose deficiency frequently associated with mental retardation and Macular abnormality-Lenticular lesions-Myoclonus syndrome. dysmorphic features, whereas the infantile form of type II usually begins during the first year and is invariably associated with visceromegaly, hearing loss, and dysmorphic changes. Lowden and O'Brien (1) summarized the 37 known and suspected cases of sialidosis through 1979, including 18 patients with type I and 19 pa tients with type II disease. We report two addi tional patients, one best classified as haVing type I and the other as having features of juvenile type II disease. Using our two patients and 48 others from the medical literature, we attempt to deter mine the frequency of various ophthalmologic ab From the Departments of Ophthalmology (l.S.T.), Neu normalities in this disorder. rology (E.S.R.). and Pediatrics (B.K.B.), Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina. Dr. Till's present address is The Lewis-Gale Clinic, CASE REPORTS Salem, Virginia. Address correspondence and reprint requests to Dr. E. S. Patient 1 Roach, Department of Neurology, Bowman Gray School of Medicine. Wake Forest University, Winston-Salem, NC 27103, A 16-year-old white girl was evaluated for a 2 year history of progressive ataxia. Her gait was so NEURO-OPHTHALMIC MANIFESTATIONS OF SIALIDOSIS 41 unsteady that she frequel1tlyfelI,andduring the three periCeritral scotomata in each eye, but there previous few months she had also noticed trouble , was some difficulty in testingin that the patient holding onto objects: We were unable todocu-__ was- slow to respond.-On slit lamp examination, ment intellectual deterioration, since the patient there were two distinct anterior stromal opacities was poorly cooperative with psychological stud in the right eye, one -.2mm andthe other 1 mm ies. Her grades in school had dropped substan in diameter (Fig. 1). N()similaropacities'were tially.sirice _the time of herdiagnosis, perhaps found in-the left eye:-Theanteriorchamberswere owing inpartto her frequent absencesfrom school deep and dear, and the irides were normal. Both rather than to intellectual deterioration. She had no lenses had fine opacities in a lamellar distribution. family history of gait disturbance, but a-younger The vitreous was normaL Tonometry by applana brother (patient 2) had a'long history of nonpro- tion showed intraocular pressures of 14 mmHg in gressivemental retardation. - - the right eye and 17 mmHg inthe left eye. Both The results of general physical examination and ,maculae had thetypical cherry-red spot (Fig. 2). her-mental status were normaL She had slightly The retinal vasculature was normal, and l1oabnor decreased strength in the hands and increased malities of the peripheral retina were evident. The muscle tone inthe legs. The deep tendon reflexes discs had large physiologic cups. were hyperactive, especially in the legs,where The results of laboratory studies, including com ankle clonus waspresenLA restingtremor,'which puterized cranial tomography, brainstem and so worsened with movement, was noted. The gait matosensory evoked responses, electroencephalo- was wide-based and markedly ataxic; and she 'gram,serum chemistry, peripheral cell count, could •not tandem walk. Her cranial nerves and rheumatoid faCtor; _and sedimentation rate, were sensation were normal. normal. The chest radiograph --revealed mild sco Ophthalmologic examination showed -- heibest Iiosisbuf was otherwise normal. Visual evoked corrected visual acuity to be 20/30 in each eye with responses were minimally-abnormal because of -1.50~3.00 x 180 in ,the ,right eye and-4.00 bilaterally delayed conduction times. Enzyme -: 2.50 x 180 in the left eye. Her color vision'was studies on cultured skin fibroblasts revealed 3.3% poor: orily two of 18 Ishihara jsochromaticplates of normal neuraminidase activity with normal ac were correctly named with either eye, The pupils tivity of other lysosomal hydrolases. were 3 mmineach.eyeand.normallyreactive with no afferent defect. The lids were normal. The eye movements were normal, although an end-point .- . .- -... .- 'nystagmus was present on horizontal gaze. Visual A12~year-oldboy, a sibling of patient -I,had a fields with _the Goldman perimeter demonstrated history of poor intellectual development dating to

FIG. 1. -Cor~MI'o~acitie~ (arrow) of~a ient1.

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, CiiIlN~uro-oplrt;lQh~ol. V~1. i,No_ 1, 1987

NEURO-OPHTHALMIC MANIFESTATIONS OF SIALIOOSIS 43

only rarely do they have mental retardation, hear scribed in several patients, and in our first patient, ing loss, dysmorphic features, or visceromegaly. these lesions were found in a lamellar distribution Patients with type II juvenile sialidosis typically in the area of the adult nucleus. Other authors have dysmorphic features but not visceromegaly, have reported opacities in the anterior and poste whereas children with infantile type II disease rior subcapsular spaces, or white flake-like lesions have hearing loss, dysmorphic features, viscero in the adult lens reminiscent of those seen with megaly, and the onset of symptoms during the myotonic dystrophy (9). Neuraminic acid-con first year of life. Our two patients illustrate the dif taining macromolecules are an integral component ficulty of a classification scheme based solely on of the normal lens (10,11), and it is not surprising clinical features: although they were siblings, each that these opacities are so common in sialidosis. had features of a separate clinical subtype of neur Optic atrophy may result from the accumula aminidase deficiency. An adequate explanation for tion of metabolic products in the ganglion cells, these dissimilar presentations will probably de leading to axonal atrophy. Visual field defects pend on additional delineation of the genetic and have included paracentral scotomata (9,12,13), biochemical basis for the subtypes. centrocecal defects (14), and enlargement of the Many of the reported patients with neuramini blind spot (15). dase deficiency have had incomplete documenta While most hereditary neurologic disorders of tion of their ophthalmologic findings, including children are not currently treatable, the early our second patient, who was retarded and would diagnosis of these disorders is important for estab not cooperate with slit lamp examination. The fre lishing the prognosis and for proper genetic coun quency of various ophthalmologic findings in the seling. Recognition of the typical ocular manifesta adequately documented patients is summarized in tions of neuraminidase deficiency by the ophthal Table 2. Regardless of the subtype, most affected mologist may help to establish the diagnosis of patients have cherry-red macular lesions. The this recently described disorder. three patients with documented absence of these lesions were type II patients at the extremes of Acknowledgment: We thank Mr. Marshall Tyler for the corneal and retinal photographs. age: one patient was 48 years old (5) and two were 8 months (6) and 15 months (7) of age. There have been reports of cherry-red spots fading or even REFERENCES disappearing over time in patients with Tay-Sachs 1. Lowden JA, O'Brien J. Sialidosis: a review of human neur disease (3) and in those with both type I (4) and aminidase deficiency. Am JHum Genet 1979;31:1-18. type II juvenile sialidosis (8). Progressive deterio 2. Durand P, Gatti R, Cavalieri 5, et al. Sialidosis (mucolipi ration of vision is commonly noted, but the visual doses I). Helv Paediatr Acta 1977;32:391-400. 3. Kivlin JD, Sanborn GE, Myers GG. The cherry-red spot in acuity may be normal or only mildly diminished, Tay-Sachs and other storage diseases. Ann Neural 1985;17: as in our first patient. Corneal opacities have been 356-60. reported with all clinical types of neuraminidase 4. O'Brien JS. The cherry red spot-myoclonus syndrome: a newly recognized inherited lysosomal storage disease due deficiency, though they are more commonly seen to acid neuraminidase deficiency. Clin Genet 1978;14:55-60. in type II than type I disease. The unilateral cor 5. Miyatake T, Atsumi T, Obayashi T, et al. Adult type neu neal opacity in our first patient is somewhat sur ronal storage disease with neuraminidase deficiency. AmI Neural 1979;6:232-44. prising, though we suspect that with time the le 6. Kelly TE, Graetz G. Isolated acid neuraminidase defi sions will be evident bilaterally. ciency. Am J Med Genet 1977;1:31-46. Fine punctate lenticular opacities have been de- 7. Aylsworth AS, Thomas GH, Hood JL, Malouf N, Libert J. A severe infantile sialidosis: clinical, biochemical and mi croscopic features. JPediatr 1980;96:662-8. TABLE 2. Ophthalmologic findings in sialidosis· 8. Thomas GH, Goldberg MF, Miller CS, Reynolds LW. Neur aminidase deficiency in the original patient with the Gold Type II berg syndrome. Clin Genet 1979;16:323-30. 9. Thomas PK, Abrams JD, Swallow 0, Stewart G. Sialidosis Type I Juvenile Infantile type I: cherry red spot-myoclonus syndrome with siali dase deficiency and altered electrophoretic mobilities of Decreased acuity 15/19 11/11 NR some enzymes known to be glycoproteins. J Neural Neuro Loss of color vision 4/4 2/2 NR surg Psychiatry 1979;42:873-80. Lenticular lesions 9/10 5/6 2/2 10. Dische Z. Glycoproteins of the lens. Invest Ophtlwlmal Cherry-red macula 25/25 13/14 3/5 1965;4:174-80. Visual field defect 7/8 1/1 NR 11. Hadad H, Becker B. Distribution of sialic acids in the Optic atrophy 7/10 3/3 NR human eye. Arch OphthalmoI1961;65:563-4. Corneal lesions 3/16 11/14 2/4 12. Sogg RL, Steinman L, Rathjen B, Tharp BR, O'Brien JS. Cherry-red spot-myoclonus syndrome. Ophthalmology NR, not reported. 1979;86:1861-73. . • Information from references 1, 2, 4, 5-9, 12-38. 13. Steinman L, Tharp BR, Dorfman L}, et al. Peripheral neu-

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ropathy in the cherry-red spot-myoclonus syndrome. matic studies of a new variant of GMt gangliosidosis in an Ann Neural 1979;7:450-6. older child [abstract). Pediatr Res 1977;11:407. 14. Tittarelli R, Giagheddu M, Spadetta V. Typicalophthalmo 26. Kobayashi T, Ohta M, Goto 1, Tanaka Y, Kuroiwa Y. Adult scopic picture of "cherry red spot" in an adult with the type mucolipidosis with beta-galactosidase and sialidase myoclonic syndrome. Br JOphthamaI1966;50:414-20. deficiency. JNeural 1979;221:137-49. 15. Thomas GH, Tipton RE, Ch'ien LT, Reynolds LW, Miller 27. Kuriyama M, Miyatake T, Owada M, Kitagawa T. Neur CS. Sialidase (alpha-N-acetyl neuraminidase) deficiency: aminidase activities in sialidosis and mucolipidosis. J the enzyme defect in an adult with macular cherry-red Neural Sci 1982;54:181-7. spots and myoclonus without dementia. Clin Genet 1978; 28. O'Brien JS. Neuraminidase deficiency in the cherry red 13:369-79. spot-myoclonus syndrome. Biachem Biaphys Res Cammun 16. Anderson B, Margolis G, Lynn WS. Ocular lesions related 1977;79:1136-40. to disturbances in fat metabolism. Am JOphthalmaI1958;45: 29. O'Brien JS, Warner TG. Sialidosis: delineation of subtypes 23-41. by neuraminidase assay. Clin Genet 1979;17:35. 17. Den Tandt WR, Leroy JG. Deficiency of neuraminidase in 30. Okada S, Kato TA, Miura S, et al. Hypersialyloligosaccha the sialidoses and the mucolipidoses. Hum Genet 1980;53: riduria in mucolipidoses: a method for diagnosis. Clin Chim 383-9. Acta 1978;86:159-67. 18. Federico A, Cecio A, Battini GA, Michalski Je, Strecker G, 31. Orii T, Minami R, Sukegawa K, et al. A new type of muco Guazzi Gc. Macular cherry-red spot and myoclonus syn lipidosis with beta-galactosidase deficiency and glycopepti drome. JNeural Sci 1980;48:157-69. duria. Tahaku JExp Med 1972;107:303-15. 19. Franceschetti S, Uziel G, Di Donato S, Caimi L, Avanzini 32. Quazzi GC, Ghetti B, Barberi F, Cecio A. Myoclonus-epi G. Cherry-red spot myoclonus syndrome and alpha-neur lepsy with cherry-red spot in adult: a peculiar form of mu aminidase deficiency: neurological, pharmacological and copolysaccharidosis. Acta Neural (Napoli) 1973;28:542-9. biochemical study in an adult. JNeural Neurasurg Psychiatry 33. Rapin I, Goldfisher S, Katzman R, Engel J, O'Brien JS. The 1980;43:934-40. cherry-red spot-myoclonus syndrome. Ann Neural 1978; 20. Goldstein ML, Kolodny EH, Gascon GG, Gilles FH. Mac 3:234-42. ular cherry-red spot, myoclonic epilepsy, and neurovis 34. Spranger J, Gehler J, Cantz M. Mucolipidosis I-a siali ceral storage in a 17-year old girl. Trans Am Neural Assac dosis. Am JMed Genet 1977;1:21-9. 1974;99:110-2. 21. Hambert 0, Petersen I. Clinical, electroencephalographical 35. Susuki Y, Nakamura N, Fukuoka K, Shimada Y, Uono M. and neuropharmacological studies in syndromes of pro Beta-galactosidase deficiency in juvenile and adult pa gressive myoclonus epilepsy. Acta Neural Scand 1970;46: tients. Hum Genet 1977;36:219-29. 149-86. 36. Swallow DM, Evans L, Stewart G, Thomas PK, Abrams JD. 22. Hong VN, Beauregard G, Potier M, et al. Studies on the Sialidosis type I: cherry red spot-myoclonus syndrome sialidoses. Biachim Biaphys Acta 1980;616:259-70. with sialidase deficiency and altered electrophoretic mo 23. Hootgeveen AT, Verheijen FW, d'Azzo A, Galjaard H. Ge bility of some enzymes known to be glycoproteins. Ann netic heterogeneity in human neuraminidase deficiency. Hum Genet 1979;43:27-35. Nature 1980;285:500-1. 37. Symonds C. Myoclonus. Med JAust 1954;1:765-8. 24. Itoyama Y, Goto F, Kuroiwa Y, Takeichi M, Kawabuchi M, 38. Winter RM, Swallow DM, Baraitser M, Purkiss P. Sialidosis Tanaka Y. Familial juvenile neuronal storage disease. Arch type 2 (acid neuraminidase deficiency): clinical and bio Neural 1978;35:792-800. chemical features of a further case. Clin Genet 1980;18:203 25. Justice PM, Wenger DA, Naidu S, Rosenthal 1M. Enzy- 10.

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