SIMULTANEOUSLY AND INDEPENDENTLY several investigators found and identified the abnormal urinary metabolite excreted by patients with the disease which we now know as homocystinuria.1 So prominent are the ocular manifestations of this condition that one of the initial cases was discovered at an eye hospital.3 Additional cases were soon found and studied in Great Britain, Boston, New York, Philadelphia, Baltimore, Bethesda, Ann Arbor and El Paso.410 The condition represents another of Garrod's "inborn errors of metabolism" and is now well characterized clinically and biochemically.
Of approximately 3,000 mentally defective individuals studied in Northern Ireland 10 had homocystinuria.4 Thus, the disease may rank as the second most common metabolic disease associated with mental retardation (phenylketonuria being the first). This report presents the ocular findings in thirty-one cases of homocystinuria, three of which have not been previously described.
The most striking biochemical abnormalities are the presence of homocystine in urine and excess homocystine and methionine in blood. The catabolism of methionine is not completely understood, but the most important pathways appear to be those shown in (Figure 1). Methionine donates a methyl group (via several steps) to form homocysteine. Though this series of reactions is not reversible homocysteine can be remethylated to methionine via a different pathway. It can also be oxidized to homocystine, which is then excreted in the urine. A major route for homocysteine is condensation with serine to form cystathionine, catalyzed by cystathionine synthase. Mudd, Finkelstein, Irreverre and Laster have shown that this enzyme is absent or almost absent from patients with the disease "homocystinuria."9· u Consequently, metabolites "above" the metabolic block are present in increased amounts (methionine and homocystine in serum, homocystine in urine) and those "below" are decreased (cystathionine - especially low in brain, where it is normally found in relatively high concentration,1,2,21 and cystine - low in urine, plasma and red blood cells.3
Fig. 1: Scheme of methionine metabolism.* The presence of an abnormality in cystathionine synthase, as occurs in homocystinuria, would be expected to result in elevation of methionine and homocysteine, and deficiency of cystathionine and cysteine. This scheme omits several important steps and is intended to be a summary rather than a detailed outline of the pathway.
* Several important steps are omitted in the scheme, and it serves as a summary rather than a detailed outline of the pathway.
General Clinical Findings
The appearance of a homocystinuric patient is fairly characteristic (Table 1). Important findings are fair hair and skin, rosy cheeks, dislocated lenses, mental retardation, and flat-footed, broad-based gait. Most have knock-knees and about half resemble individuals with Marfan's syndrome. Half will have convulsions and will die in childhood of thromboembolic disease. All findings may not be present in a particular individual.
Proper diagnosis of homocystinuric disease should come easily to the ophthalmologist because the eyes are strikingly involved (Table 2). Exact incidence of ocular findings is difficult to ascertain for the patients are usually young, retarded and Photophobie; furthermore, not all cases have been checked by ophthalmologists. Except for an infant dying in the first month of life who consequently may not have been properly examined13 and a 24-year-old, clinically normal woman who excreted only small amounts of homocystine3 all patients have had partially or completely dislocated lenses; they may be dislocated in any direction and may produce glaucoma. Several other ocular signs seem to be of importance in addition to dislocated lenses. Most cases have lightly pigmented iris stroma. Several eyes have been removed because of glaucoma.* Cataracts have been noted in four cases,4*18 and optic atrophy apparently unrelated to glaucoma has been seen in two others.3*14 One case each of keratitis, iritis, retinal detachment and microphthalmos has been described.4,15 Lens extraction, performed in about one quarter of the cases, has not been associated with unexpected ocular complications though several patients have died of thromboembolic disease in the postoperative period. The lenses have been removed intracapsularly with ease because of the weak zonules.
GENERAL CLINICAL FINDINGS IN HOMOCYSTINURIA
OCULAR FINDINGS IN HOMOCYSTINURIA
We have had the opportunity to examine three patients previously diagnosed as Marian's syndrome who were found by Schimke, McKusick and Pollack to have homocystinuria.8 Their ages ranged from 20 to 24. Ocular findings will be reported in detail because they differ with findings tabulated on the basis of a review of other cases. In none was the best-corrected visual acuity better than 20/30, and in two it was worse than 20/70. Intraocular pressure was normal in two cases. The third patient had previously had her right lens extracted and had developed minimal band keratopathy though the anterior chamber was deep and vision 20/30; no surgery had been performed on the left eye; intraocular pressure was six mm Hg. in both eyes (applanation). All irides were slightly muddy due to minimal atrophy. Two lenses had been extracted, three had dislocated into the vitreous (Fig. 2), and one had absorbed spontaneously. Two of the lenses still present were perfectly clear whereas the third was densely cataractous (Fig. 3). Four of the optic discs appeared normal. The right disc of the patient with hypotony was moderately atrophic, the left disc was mildly hyperemic and edematous, probably secondary to the low pressure. The blood vessels and maculae were normal.
All three patients showed retinal changes. In one, mild peripheral cystic degenerative changes with retinal thinning were noted and several small elevations, felt to be schisis rather than detachment, extended from the oral bays towards the pars plana. Similar changes were noted in the second case, who in addition had a large, round immobile cyst at the ora superiorly. In the third, sectors of low retinal elevation were present in the right eye superonasally and inf erotemporally, consisting of many white, loculated, gliotic-appearing cysts about twice the size of the disc (Fig. 4). Pigment rimmed the lesions and was scattered through them. No holes were seen and the elevated retina did not shift with eye movement. In the left eye of this patient a large, incomplete choroidal coloboma was present inferiorly. All eyes had a band of relative depigmentation' at the equator, making the already lightly-pigmented fundi appear almost albinotic. Electroretinography performed on a patient with extensive retinal changes showed only nonspecific voltage decrease.
All patients with dislocated lenses and mental retardation are suspect of having homocystinuria, especially if blue-eyed, blond-haired and rosy cheeked. Undoubtedly some patients with homocystinuria will have dislocated lenses without retardation, for all graduations of the disease may occur. The variability of signs is well demonstrated by a family studied by us.3 The propositus was a child with "classic" clinical and biochemical changes of homocystinuria. Her cousin excreted small amounts of homocystine but had no other clinical or biochemical abnormalities. Her parents appeared completely normal. Biochemical investigations at the National Institutes of Health'1 showed that the severity of disease was related to the degree of abnormality of the responsible enzyme, cystathionine synthase. This variability of expression is expected, for it is known that individuals with the same genetic make-up may express their genes differently depending on environment; complement of other genes, etc. Moreover, in the family just mentioned other factors (such as multigenic defects) may also play a role.
Fig. 2: Clear dislocated lens in the vitreous. Intraocular pressure 18 mm Hg. Visual acuity 20/80. The eye is in marked downward gaze.
Fig. 3: Cataractous dislocated lens in the vitre orn. Intraocular pressure ? mm Hg. Visual acu ity 20/40. The eye is in marked downward gaze.
Fig. 4: Drawings of the fundus of a 24-year-old woman with homocystinuria. Retinal elevation is greatest peripherally. Mild optic atrophy and microcystoid degeneration are present. Intraocular pressure 6 mm Hg. Visual acuity 20/30.
The inconstancy of findings means that homocystinuria is frequently undiagnosed or misdiagnosed, so accurate appraisal of the incidence of the condition is difficult. A simple, sensitive test such as the ferric chloride test for phenylketonuria would greatly facilitate proper diagnosis and study. The optimum time for such testing is in the immediate neonatal period before symptoms appear, when proper diet conceivably might allow normal development.
The existence of an individual who excretes homocystine in her urine but who is relatively free of other defects raises the question as to proper naming of the disease. It has not been proven that presence of homocystine in urine signifies disease. However, until the complete biochemical nature of the abnormality is known homocystinuria, or more specifically "homocystinuric disease" seems acceptable.
The differential diagnosis of homocystinuria deals primarily with its two major manifestations, mental retardation and dislocated lenses. There is nothing characteristic about the mental retardation in homocystinurics, but its presence in conjunction with dislocated lenses is of great diagnostic significance. Many other metabolic causes of mental retardation are associated with other ocular findings (Hurler's Disease, Wihon's Disease, Tay Sachs' Disease, Fabry's Disease, etc.) .
Bilaterally dislocated lenses have various causes. Probably most common is the dominantly inherited condition in which the lenses are dislocated con geni tally.16 Dislocation later in life, unassociated with other findings, may also be familial, though usually is inherited in a recessive fashion.17 At least % of the cases of Marfan's syndrome, with their rather typical cardiovascular and skeletal abnormalities, have subluxated, lenses.18 Patients with Marchesani's syndrome have dislocated lenses, though their short stocky build, round heads and stubby hands make them clinically the "opposite" of Marian's.19 Syphilis has been suggested as an etiologic factor but evidence is certainly not conclusive.20 Trauma may also produce bilaterally dislocated lenses, though usually only one eye is affected.
Most patients with homocystinuria have had both dislocated lenses and mental retardation, but it is expected that some patients will have only one or the other manifestation. Indeed, we have already reported the first case in which homocystinuria was found without any other apparent defect.-2 In this regard the less commonly reported ocular signs may prove of diagnostic importance, for retinal cysts or optic atrophy, etc., may signal the presence of the basic biochemical abnormality.
Even when a diagnosis other than homocystinuria is readily apparent the possibility of an underlying biochemical defect should be borne in mind and appropriate studies conducted where possible. For example, in this series of thirty-one patients with homocystinuria the three new cases and six of the old had previously been classed as Marian's syndrome.
Pathogenesis of Ocular Defects
Methionine metabolism of ocular tissue has been scantily studied. Nover and Schultze found incorporation of "S3s-thioamino-acids" most intense in the choroid and ganglion cell layer of the retina." Dardenne and Kirsten investigated sulfur transfer in the lens and identified most of the major compounds of methionine metabolism in this organ.24 Barber demonstrated conversion of S'i5-methionine to cystathionine, cysteine and glutathione in the lens.25 This information is not sufficient to allow construction of a theory regarding pathogenesis of the cystoid degenerative changes in the retina or the abnormalities in the zonular fibers both of which have been noted on pathologic examination of the globes. 2a Bembridge et al showed that zonular and coarse vitreous fibers are both resistant to collagenase.27 These observations have been partially confirmed.25 The results of preliminary analyses of material remaining after collagenase digestion of bovine and rabbit lens capsules suggest that the amino acid composition of zonular fiber is more similar to elastin than to collagen or vitreous residual protein.28,29 Perhaps most significant is the finding that zonular protein contains cystine, which is not present in either elastin or collagen. Cystine, in fact, appears to be the limiting amino acid, so that deficiency might be expected to affect zonular development, and consequently to predispose to lens dislocation.
If the composition of the basement membrane of ciliary epithelium is similar to the structural elements of the peripheral retina it is possible that the cystoid degenerative changes may also be secondary to cysteine deficiency. Pappas and Smelser have shown that zonular fibers are continuous with the basement membrane of the. ciliary epithelium*0 and so they may have a similar biochemical composition. Whatever their initial cause, these cystoid changes would seem to be related to the cysts and "schisis" seen in the peripheral retina.
Since the optic nerves are a specialized part of the brain it is perhaps reasonable to assume that they both share the same high cystathionine content. Optic atrophy in homocystinurics may consequently be the result of the cystathionine deficiency these patients experience. Most of the other ocular findings (glaucoma, keratitis, iris atrophy, etc.) are probably related to abnormal anatomic conditions, specifically the dislocated lenses, and not to particular biochemical defects.
Biochemical etiologies of disease are being found with increasing frequency. Only by enlightened clinical suspicion can the presently established conditions be diagnosed and the myriad as-yet-uncharacterized diseases be discovered.
Homocystinuria is an established clinical entity. It appears to be the result of deficient cystathionine synthase, an enzyme involved in the metabolism of sulfur-containing amino acids (methionine, homocysteine, cystathionine and cysteine) .
Clinical findings in twenty-eight previously discovered cases are reviewed; they include mental retardation, fair hair and skin, rosy cheeks, abnormal gait, thrombophlebitis, convulsions and premature death. Ocular manifestations are common; dislocation of the lenses has been noted in over 90 per cent of the cases; myopia, glaucoma, keratitis, iritis, cataract and optic atrophy have also been described.
Findings in three previously unreported cases are detailed; in addition to posteriorly dislocated lenses (3/3) they include retinoschisis (3/3) , cataract (1/3) and optic atrophy (1/3) . It may be that these abnormalities will be present in some homocystinuric patients who do not have the two hallmarks of the disease, namely, mental retardation and dislocated lenses.
The existence of an individual who excretes homocystine in the urine but is otherwise apparently free of significant disease is pointed to as an example of the variability found in this disease.
Differential diagnosis and possible pathogenesis of the ocular findings are discussed.
1. Field, C. M. B., Carson, N. A. J., Cusworth, D. C, Dent, C. E., and Neill D. W.: Abstr. X Internat. Cong. Ped. (Lisbon) p. 274, 1962.
2. Gerritsen, T., Vaughn, J. G., and Waisman, ?. ?.: The Identification of Homocystine in the Urine. Biochem. Biophys. Res. Comm. 9:493-496, 1962.
3. Spaeth, G. L., and Barber, G. W.: Homocystinuria in a Mentally Retarded Child and Her Normal Cousin. Tr. Am. Acad. Ophthal. Oto. (in press).
4. Carson, N. A. J., Dent, C. E., Field, C. M. B., and Guall, G. E,: Homocystinuria. J. Ped. 66:565584, 1965.
5. Komrower, G. M., and Wilson, V. K.: Homocystinuria. Proc. Royal Soc. Med. 56:993-997, 1963.
6. White, H. H., Araki, S., Thompson, H. L., Rowland, L. P., and Cowen D.: Homocystinuria. Tr. Am. Neurol. Assoc. 89:24-27, 1964.
7. Kennedy, C: Quoted in White, H. H., Araki, S., Thompson, H. L., Rowland, L. P. and Cowen D: Homocystinuria. Tr. Am. Neurol. Assoc. 89:24-27, 1964.
8. Schimke, R. N., McKusick, V., and Pollack, ?.: Homocystinuria simulating Marfan's Syndrome. Trans. Am. Acad. Physicians. 1965 (in press).
9. Mudd, S. H., Finkelstein, J. D., Irreverre, F., and Laster, L.: Homocystinuria: An Enzymatic Defect. Science 143:1443-1445, 1964.
10. Falls, H. F.: A personal communication.
11. Finkelstein, J. D., Mudd, S. H., Irreverre, F., and Laster, L.: Homocystinuria Due to Cystathionine Synthetase Deficiency: The Mode of Inheritance. Science 146:785-787, 1964.
12. Gerritsen, T., and Waisman, H. A.: Homocystinuria: Absence of Cystathionine in the Brain. Sci- I enee 145:588, 1964.
13. Gerritsen, T., nd Waisman, H. A.: Homocystinuria, An Error in the Metabolism of Methionine. Pediat. 33:413-420, 1964.
14. Kennedy, C: A personal communication.
15. Arnott, E. J., and Greaves, D. P.: Ocular Involvement in Homocystinuria. Brit. J. Ophthal. 48: 688-690, 1964.
16. Falls, H. F., and Cotterman, C. W.: Genetic studies on ectopia lentis: A Pedigree of Simple Ectopia of the Lens. Arch. Ophthal. 30:610-620, 1943.
17. Vogt, ?.: Dislocatio Lentis Spontanea als Erbliche Krankheit. Ztschr. Augenheilk. 14:153-165, ' 1905.
18. McKusick, V. ?.: Rentable disorders of connective tissue. St. Louis, Mosby, 1956, p. 43.
19. Marchesani, O.: Brachydaktylie und angeborene Kugellinse als Systemerkrankung. Klin Mbl. Augenheilk. 103:393-406, 1939.
20. Smith, J. L.: The TPI Test in Ophthalmology. Am. J. Ophthal. 57:973-977, 1964,
21. Tallau, H. H., Moore, S., and Stein, W. H.: L- Cystathionine in Human Brain. J. Biol. Chem. 230: 707-716, 1958. i
22. Spaeth, G. L., and Barber, G. W.: Homocystinuria, A New Syndrome. Wills Eye Hospital Annual Clinical Conference, February, 1963.
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24. Dardenne, U., and Kirsten, G.: Presence and Metabolism of Amino Acids in Young and Old lenses. Exp. Eye Res. 1:415-421, 1962.
25. Barber, G. W.: Unpublished results.
26. Ashton, N.: A personal communication.
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29. Young, R. G., Williams, H. H: Gelatinous Protein of Vitreous Body. A.M. A. Arch. Ophthal. 52: 593-595, 1954.
30. Pappas, G. D., and Smelser, G. K.: Studies on the Ciliary Epithelium and the Zonule. Am. J. Ophthal. 46:299-318 (Nov., Pt. 2), 1958.
GENERAL CLINICAL FINDINGS IN HOMOCYSTINURIA
OCULAR FINDINGS IN HOMOCYSTINURIA