Journal of Neuro-Ophthalmology, June 1988, Volume 8, Issue 2

Saccadic Abnormalities in Nephropathic Cystinosis

Cystinosis is an autosomal recessive metabolic disorder in which nonprotein cystine accumulates within most body tissues due to a defect in lysosomal cystine transport. The pathognomonic manifestation of cystinosis is the presence of distinctive iridescent crystals within ocular tissues. Although these crystals have been detected within the extraocular muscles, no associated abnormality of eye movement has been described. We measured horizontal saccades of 5-30 in six patients with infantile nephropathic cystinosis. Our data indicate that patients with cystinosis have slowed saccades. Saccadic duration, peak velocity, peak acceleration, and peak deceleration were all abnormal.

Journal of Clinical Neuro-ophthalmology 8(2): 115-119, 1988. Saccadic Abnormalities in Nephropathic Cystinosis Barrett Katz, M.D., Ronald B. Melles, Doris A. Trauner, M.D., and Jerry A. Schneider, M.D. '9 1988 Raven Press, Ltd., New York Cystinosis is an autosomal recessive metabolic disorder in which nonprotein cystine accumulates within most body tissues due to a defect in lysosomal cystine trans­port. The pathognomonic manifestation of cystinosis is the presence of distinctive iridescent crystals within oc­ular tissues. Although these crystals have been detected within the extraocular muscles, no associated abnor­mality of eye movement has been described. We mea­sured horizontal saccades of 5-30° in six patients with infantile nephropathic cystinosis. Our data indicate that patients with cystinosis have slowed saccades. Saccadic duration, peak velocity, peak acceleration, and peak de­celeration were all abnormal. Key Words: Cystinosis-Saccades-Saccadic duration. From the Departments of Ophthalmology (B.K., R.B.M.), NeurOSCiences (B.K., D.A.T.), and Pediatrics (D.A.T., j.A.5.), UniverSity of California, San Diego, California. Address correspondence and reprint requests to Dr. Barrett Katz, UCSD Eye Center, M-OIS, LaJolla, CA 92039, U.S.A. U5 Cystinosis is an autosomal recessive metabolic disorder in which nonprotein cystine accumulates within most body tissues (1). The cystine accumu­lates within the lysosomes of cells because of a de­feet in lysosomal cystine transport (2,3). Cystinosis can be divided into two major clinical groups, nephropathic and benign. Nephropathic cys­tinosis can be further divided into infantile and late-onset (juvenile or adolescent) forms. The in­fantile is the most common and the most devas­tating. Systemic complications include the renal Fanconi syndrome with rickets, growth retarda­tion, and renal failure that necessitates renal transplantation by an average age of 10 years. The age of presenting symptoms in patients with late­onset cystinosis ranges from 4 to 25 years. Unlike patients with infantile nephropathic cystinosis, those with late-onset cystinosis do not have the complete Fanconi syndrome, and their renal failure progresses more slowly. Other patients have a completely benign form of cystinosis and are discovered by serendipity when ophthalmo­logic examination reveals characteristic cystalline opacities in the cornea and conjunctiva. Children with infantile cystinosis are now surviving to the second and third decade of life, permitting evalua­tion of the long-term effects of cystinosis on nonrenal tissues. Ophthalmic complications and impairment of visual function are common serious long-term sequelae (4). All three phenotypes of cystinosis are associated with ocular manifestations. A pigmentary retinop­athy characteristically affecting the periphery has been described in the nephropathic form of the disease (5) but not in the benign form (6). The pa­thognomonic ocular manifestation of cystinosis is the iridescent crystal deposition within the con­junctiva and cornea. Histologically, the crystals are birefringent, intracellular, and of varying form. 116 B. KATZ ET AL. Needle-shaped or fusiform crystals are seen in the cornea, whereas polymorphous, rectangular, or rhomboidal crystals infiltrate the conjunctiva (7-9). Ultrastructural analysis has shown these crystals to be intralysosomal (10,11), and crystallo­graphic analysis has shown the rectangular forms to be composed of L-cystine (12). The fusiform crystals are also assumed to be cystine, but this has never been demonstrated. Crystals have been seen in the iris, ciliary body, choroid, retinal pig­ment epithelium, sclera, episclera, and optic nerve sheath (9-14). The crystals have also been de­tected within the extraocular muscles (10,13), but no associated abnormality of eye movement has been described. Although autopsy studies on the central nervous system in cystinosis have shown high parenchymal levels of cystine (14,15); accu­mulations of cystine crystals within choroid plexus, pineal gland, and meninges (15,16); and extensive demyelination of the internal capsule and brachium pontis (17), cystinosis patients have been thought to be neurologically normal. Whereas ocular tissues are extensively involved in cystinosis, the only visual complaint is, gener­ally, photophobia. We studied a group of patients with infantile cystinosis to determine whether the infiltration of extraocular muscles by cystine crystals is reflected in altered function as studied in an eye movement recording laboratory. MATERIALS AND METHODS We evaluated six patients between the ages of 5 and 19 (mean age, 13 years) with infantile-onset nephropathic cystinosis. All had mild photo­phobia. None of the six had any complaints of dip­lopia. Patients underwent complete neuro-ophthalmo­logic evaluation. All had normal visual acuity and color vision bilaterally. Pupillary responses were normal, without evidence of afferent pupillary de­fect. All of the patients had the classic anterior segment findings of cystinosis, with crystal depo­sition in the conjunctiva and cornea. Vestibulo-oc­ular reflexes were intact. Stereo acuity was normal, and sensory testing showed normal fixa­tion without suppression or anomalous retinal correspondence. Saccades and pursuits were thought to be clinically normal and ductions full. No patient had nystagmus or other adventitious eye movements. Ophthalmoscopic evaluation re­vealed patchy depigmentation of the peripheral retina in all of the patients. There was a patchy, mottled appearance to each fundus from the mid­equator to the ora serrata. Optic nerves were of ; L, I 'I "(. l.~ normal color, contour, and capillarity. No abnor­mality of nerve fiber layer could be appreciated. The eye-movement-recording appar~tus de­tects the reflections from each eye of mfrared light-emitting diodes (18). A ~irror tra~sparen.t for visible light yet reflective for mfrared hght projects the light reflected from each iris plane onto a linear array of 1,024 photo diodes. A video signal is generated from the output of the photo diodes, and the margin of the pupil's space is determined electronically. The addresses of the appropriate diodes are read by a microprocessor, and the data are analyzed by computer. The system has a linear range of 30°, a spatial resolution of greater than O. i 0, and a temporal resolution of 4 ms. It allows for the simultaneous recording of each eye. The target stimulus was generated by a helium neon laser mounted on the recording apparatus. The laser beam was reflected by a mirror galva­nometer and projected onto a white, featureless screen in front of the subject. The target sub­tended approximately 0.2° of visual angle. Sac­cades were elicited by moving the target in hori­zontal square-wave (step) trajectories of 5-30°. We measured saccades of 5-30° in the hori­zontal meridian for each patient. We measured at least 30 adducting and abducting saccades from each patient. Data were pooled and analyzed for saccadic amplitude, saccadic duration, peak ve­locity, peak acceleration, and peak deceleration and were compared with those of 12 normal vol­unteers (mean age, 27). Data were analyzed by simple linear regression and by second-order poly­nomial regression analysis. Statistical differences between the lines of regression were tested by a general linear hypothesis (19). RESULTS The relationship between saccadic amplitude and duration for our patients with cystinosis is il­lustrated in Fig. 1. We compared the saccades of the cystinosis patients to those measured in the control population, also demonstrated in Fig. 1. Our data indicate that for all amplitudes sampled, the cystinotic patients had prolonged saccades. However, the saccadic latencies were normal in each case. A simple linear regression analysis was performed for each population. The coefficient of regression for the cystinosis population was 0.88. Th~ coefficient of regression for the normal popu­latIon was 0.95. The lines were statistically dif­ferent in elevation (p < 0.01) and in slope (p < 0.01). NEPHROPATHIC CYSTINOSIS Jl7 Amplitude (degrees) FIG. 1. Main sequence diagram illustrating the rela­tionship between saccadic amplitude and duration in a normal population and in patients with cystinOSIs. normal cystinosis 10 20 30 0+-----..-----.------, o 2.+4 h+4 4,+4 AmpliDJde (degrees) FIG. 3. Main sequence diagram illustrating the rela­tionship between saccadic amplitude and peak accel­eration in a normal population and in patients with cystinosis. cysunosis Peak acceler.ltirn (de'l/=Isex:J no""", 10 20 30 0+------,------,--_--., o 60 20 40 BO 100 Duration (milliseconds) A main sequence diagram of saccadic amplitude versus peak velocity for the patients with cys­tinosis and for the normal population is shown in Fig. 2. A second-order polynomial of re~r~ssion was fit to each population's data. The coeffiCIent of regression was 0.90 for the cystinosis population and 0.93 for the control population. The regres­sion curve for the cystinotic population differed significantly from that of the normal population (p < 0.01). Main sequence diagrams for peak acceleration and peak deceleration are shown in Figs. 3 and 4, respectively. Second-order polynomials of regres­sion were fit to the data from each population. For peak acceleration, the coefficient of regression for both curves was 0.69. For peak deceleration, the coefficients of regression for the resulting curves were 0.56 for the cystinosis population and 0.59 for the normal population. For both peak accelera­tion and peak deceleration, the curves for the pa­tients with cystinosis differed significantly from those of the normal population (p < 0.01). DISCUSSION Our data indicate that patients with cystinosis have slowed saccades. Saccadic duration, peak ve­locity, peak acceleration, and peak deceleration all differed from those in a normal population for sac­cades of all amplitudes. The mean age of our con­trol group was 27 years; the mean age of our cys­tinotic group was 13 years. Whereas our control group was not truly age-matched to our experi­mental group, previous work has demonstrated that the main sequence relationships and saccadic velocities during childhood are comparable to those recorded in adults, even in children as young as a few months of age (20). Is this demonstration of altered ocular motility a manifestation of changed peripheral ocular motor plant dynamics or of central nervous system dys­function? Disease-associated changes of orbital anatomy and the peripheral ocular motor plant have been associated with slowed saccades (21,22). The most common of these entities is thy­roid ophthalmopathy. Feldon and Unsold (22) found that peak saccadic velocities of patients with 600 nonnaJ 500 cysuno5lS 400 Peak velocity (dey",) 300 200 100 0 0 10 20 30 Pl':1k decekr.lliCln IJ,:~./~'l.:/"£'l.l 2.+4 '0 20 30 q'sunOS1S Amplitude (degrees) FIG. 2. Main sequence diagram illustrating the rela­tionship between saccadic amplitude and peak ve­locity in a normal population and in patients with cys­tinosis. Amphtude (u.::greol FIG. 4. Main sequence diagram illustrating the rela­tionship between saccadic amplitude and peak de­celeration in a normal population and in patients with cysti nosis. JClill Nellro-oplrtha/mol. Vol. 8. No.2. 1988 118 B. KATZ ET AL. Graves' ophthalmopathy were substantially lower than those of controls. Other clinical syndromes associated with changed properties of the orbital plant and slowed saccades include the chronic progressive external ophthalmoplegias, oculo­pharyngeal muscular dystrophy, and myotubular myopathy (21). Francois et al. (8) described crystalline material within the extraocular muscles of cystinotics. Wan et a1. (13) also noted yellow crystalline material within the extraocular muscles at the time of sur­gery in a patient with infantile cystinosis. Biopsies of other skeletal muscles in patients with infantile cystinosis have shown increased amounts of cys­tine (23). The infiltration of extraocular muscles by cystine may cause decreased elasticity (increased stiffness) of the muscle fibers with consequent slowing of eye movements. This infiltration of ex­traocular muscle by cystine crystals may be analo­gous to the infiltration of the iris that has been postulated to culminate in posterior synechiae and angle closure glaucoma (13). Diseases of the central nervous system asso­ciated with slowed saccades include ataxia telangi­ectasia (24), Huntington's disease (25), parame­dian pontine reticular formation lesions, progres­sive supranuclear palsy (26), and spinocerebellar (27) and olivopontocerebellar degenerations (28,29). Cystinosis has been found to affect the central nervous system in some patients (30,31), and some older patients with infantile-onset nephropathic cystinosis have recognizable abnor­malities of both gray and white matter on com­puter tomography and magnetic resonance imaging (B. Katz, unpublished observation). It may be that brainstem structures or frontal eye fields are damaged by the systemic cystinotic pathophysiology. Slowed saccades have been reported in another inborn error of metabolism, hepatolenticular de­generation (Wilson's disease) (32). It is interesting to note that the renal Fanconi syndrome, a central feature of infantile nephropathic cystinosis, has also been described in patients with Wilson's dis­e. ase (.33-35). Cystine, which accumulates in cys­tInOSIS, and copper, which accumulates in Wils?~'s disease, are both inhibitors of sulfhydryl­requmng enzymes. Several other compounds that can cause the renal Fanconi syndrome are also in­hibitors of such enzymes and may playa role in the development of this syndrome (36). One can only speculate whether or not this common chem­ical froperty of both cystine and copper plays a role In the slowed saccades seen in these diseases. Abnormalities of eve movements are also seen in Gaucher's disease and Niemann-Pick disease, each of which results from the storage of abnormal lipid within lysosomes. In Gaucher's disease, there is often a progressive disturbance of hori­zontal conjugate gaze (an ocular motor apraxia) (37), and in patients said to have chronic neuron­opathic Niemann-Pick disease (type C) there is often ophthalmoplegia for vertical gaze (38). When saccades are slowed and the range of eye movements is limited, the slowed saccades usually reflect peripheral ocular motor abnormalities. When these slowed saccades occur with full range of ocular motility, there is usually central nervous dysfunction. We suspect that the slowed eye movements of patients with cystinosis may result from the dual mechanism of brain saccadic gener­ator dysfunction and changed ocular motor plant dynamics. Acknowledgment: This work was supported in part by Veterans Administration medical research funds. The authors acknowledge the statistical consultation of Charles Berry, Ph.D., Department of Community and Family Medicine, University of California at San Diego School of Medicine. REFERENCES 1. Schneider JA, Schulman JO. Cystinosis. In: Stanbury JB, Wyngaarden JB, Fredrickson OS, et al., eds. The metabolic basis of inherited disease. New York: McGraw-Hill, 1983: 1844-66. 2. Jonas AJ, Smith ML, Allison WS, Laiking PE, Greene AA, Schneider JA. Protontranslocating ATPase and lysosomal cystine transport. JBioi Chem 1982;258:11727. 3. Jonas AJ, Smith MO,. 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