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DISCUSSION OF PRESENTATION BY DR RiCHARD L. SOGG ET AL
MORTON F. GOLDBERG, MD CHICAGO
ALMOST 100 years ago, Warren Tay published a description of the macular cherry red spot in the very first issue of the Transactions of the Ophthalmological Society of the United Kingdom.! Subsequently, generations of ophthalmologists have more or less automatically associated a cherry red spot with a diagnosis of Tay-Sachs disease, also known as familial amaurotic idiocy. From diagnostic and prognostic points of view, this association is exceedingly risky, because some diseases with cherry red spots have neither blindness nor dementia. The cherry red spot, which represents abnormal storage of complex macromolecules in perifoveal ganglion cells, is seen in a variety of disorders, including Niemann-Pick disease, Sandhoff disease, Gaucher disease, GM1-gangliosidosis, and mucolipidosis type J.2
It is clearly established that genetic heterogeneity characterizes inborn errors of metabolism, that is, a group of inherited diseases may resemble each other clinically but have fundamental genetic and biochemical di:fferences.3 If observed closely enough, the differences may be seen even with ordinary techniques of history taking and physical
Submitted for publication Oct 24, 1978.
From the Department of Ophthalmology, Univer· sity of lllinois Eye and Ear Infirmary, Chicago.
Reprint requests to Department of Ophthalmology, University of Illinois Eye and Ear Infirmary, 1855 West Taylor Street, Chicago, IL 60612 (Dr Gold· berg).
examination. Such is the case in the disease presented here by Dr Sogg and associates, but, even here, precise diagnosis-and then proper clinical and genetic counseling-requires sophisticated techniques of electron microscopy and particularly biochemistry. In contrast to mucolipidosis type J4 and a similar syndrome described by us in 1971,2 the disease reported by Dr Sogg and associates and by others5· 7 is characterized by normality of intellect, the skeleton, facial appearance, corneal clarity, and levels of ,a-galactosidase.
Knowledge of the precise enzyme deficiency-in this case, neuraminidase-is usually sufficient for a specific clinical diagnosis. It is of considerable interest, however, that a handful of other diseases is also known to have inherited deficiencies of neuraminidase (either primary or secondary to another, more fundamental enzyme defect).8 One such disease is mucolipidosis type I,4 a disorder that shares certain characteristics of both the mucopolysaccharidoses and the sphingolipidoses and that is characterized by a Hurler-like facies, skeletal dysplasia, corneal clouding, and death by the end of childhood.9 In mucolipidosis type I, all other lysosomal hydrolases studied thus far have not been deficient,10 suggesting that the neuraminidase deficiency represents the primary genetic defect.
Another disease characterized by neuraminidase deficiency was de-
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1872 MORTON F. GOLDBERG OPHTH AAO
scribed by us in 1971,2 but seven years were required for additional biochemical research to identify the enzyme defect.U This disease is also characterized by Hurler-like facies, skeletal dysplasia and dwarfing, mental retardation, cherry red spot, myoclonus, and slight corneal clouding, but patients survive into the early or mid-twenties.12-l6 In addition to the clinical abnormalities and neuraminidase deficiency, .8-galactosidase activity was markedly reduced in our family and in other subsequently reported cases.12.13 Whether the combined enzyme de~ ficiencies represent a fundamental difference from mucolipidosis type I remains to be seen. On clinical grounds, the disease reported by Dr Sogg and associates is clearly different from the one reported by us and from mucolipidosis type I.
Although never emphasized previously, isolated case reports have recorded punctate cataracts in the cherry red spot-myoclonus syndrome,n·15 in mucolipidosis type I, 10.17 and in apparently related disorders.1B.19 A current follow-up biomicroscopic study of our family reported in 19712 similarly shows punctate cataracts in the proband (Fig 1) that were not originally present. These punctate lens opacities are reminiscent of those seen in another mucolipidosis, mannosidosis, 20 and may prove to be characteristic of this large group of storage diseases. They are not known to be characteristic of mucopolysaccharidoses or sphingolipidoses. One wonders whether Dr Sogg's patient has or will develop similar lens abnormalities. Because neuraminic acid-containing macromolecules are integral components of the lens,21.2z it is not altogether surprising that cataracts have frequently been observed in a group of diseases char-
Fig 1.-Biomicroscopic photograph of lens of patient with neuraminidase and /3-galactosidase deficiency.2• 11 Note punctate lens opacities.
acterized by neuraminidase deftciency.
There are several other inherited lysosomal storage diseases in which one enzyme defect is apparently shared between clearly different diseases; for example, iduronidase deficiency in both the Hurler syndrome and the Scheie syndrome23 and galactosidase deficiency in GM~gangliosidosis syndromes.24•25 Enzymologic technology has not yet advanced to the point of offering an incontrovertible explanation for the interesting and potentially important clinicochemical disparities among those disorders that seemingly share a common enzyme deficiency.
Proper nosology requires, in part, precision in clinical terminology. One must ask, therefore, for a more appropriate designation than "cherry red spot-myoclonus syndrome." Although this term is evocative and
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has been used by others, 5•7 it is rather nonspecific and does not differentiate among the other neuraminidase deficiency syndromes. It would be preferable for the name of this disease to reflect the precise enzyme denciency or the precise storage compound, but, as previously noted, neuraminidase deficiency is also nonspecific, as is the term "sialidosis" (representing the type of storage material).17 One can only hope for additional biochemical studies of this and related diseases.
Diagnostic splitting is more than an intellectual exercise.3 Precision in diagnosis is fundamental to proper clinical and genetic counseling and, in the future, will be required before specific enzyme or other therapy can be instituted.
REFERENCES
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2. Goldberg MF, Cotlier E, Fichenscher LG, et al: Macular cherry-red spot, corneal clouding, and beta-galactosidase deficiency: Clinical, biochemical, and electron microscopic study of a new autosomal recessive stomge disease. Arch Intern Med 128:387-398, 1971.
3. Goldberg MF: An introduction to basic genetic principles applied to ophthalmology. Trans Am Acad Ophthalmol Otolaryngol 76: OP-1137-0P-1159, 1972.
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7. O'Brien J: The cherry red spot-myoclonus syndrome: A newly recognized inherited lysosomal storage disease due to acid neuraminidase deficiency. Clin Genet 14:55-60, 1978.
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11. Thomas GH, Reynolds LW, Miller CS: Sialidase deficiency in the Goldberg syndrome. Read before the annual meeting of the American Society of Human Genetics, Vancouver, Canada, 1978.
12. Orii T, Minami R, Sukegawa K, et al: A new type of mucolipidosis with beta-galactosidase deficiency and glycopeptiduria. Tohoku J Exp Med 107:303-315, 1972.
13. Wenger DA, Tarby TJ, Wharton C: Macular cherry-red spots and myoclonus with dementia: Coexistent neuraminidase and beta-galactosidase deficiencies. Biochem Biophys Res Commun 82:589-595, 1978.
14. Suzuki Y, Nakamura N, Shimada Y, et al: Macular cherry-red spots and betagalactosidase deficiency in an adult. Arch Neurol 34:157-161, 1977.
15. Kitagawa T, Owada M, Uchida S, et al: Late onset hereditary syndrome with beta-galactosidase deficiency, cherry red macular spots, corneal opacity and coarse facies: Goldberg-Orii syndrome: An additional two cases in siblings. Read before the meeting of the International Society for Genetic Eye Disease, Tokyo, May 1978.
16. Yamamoto A, Adachi S, Kawamura S, et al: Localized beta-galactosidase deficiency. Arch Intern Med 134:627-634, 1974.
17. Durand P, Gatti R, Cavalieri S, et al: Sialidosis (mucolipidosis I). Helv Paediatr Acta 32:391-400, 1977.
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1874 MORTON F. GOLDBERG OPHTH AAO
19. Wada M, Uemura Y: Macular cherry red spot in two juvenile siblings. Metab Ophthalmol, in press.
20. Letson RD, Desnick RJ: Punctate lenticular opacities in type II mannosidosis. Am J Ophthalmol 85:218-224, 1978.
21. Haddad H, Becker B: Distribution of sialic acids in the human eye. Arch Ophthalmol 65:125-126, 1961.
22. Dische Z: Glycoproteins of the lens. Invest Ophthalmol 4:592-605, 1965.
23. Stevenson RE, Howell RR, McKusick VA, et al: The iduronidase-deficient mucopolysaccharidoses: Clinical and roentgenographic features. Pediatrics 57:111-122, 1976.
24. O'Brien JS, Norden AGW: Nature of the mutation in adult beta-galactosidase deficient patients. Am J Hum Genet 29:184-190, 1977.
25. Koster JF, Niermeijer MF, Loonen MCB, et al: Beta-galactosidase deficiecy in an adult: A biochemical and somatic cell genetic study on a variant of GM,-gangliosidosis. Clin Genet 9:427-432, 1976.
