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Ellen R. Elias, MD; Ronald M. Hansen, PhD; Mira Irons, MD; Nicole B. Quinn, OD; Anne B. Fulton, MD

Arch Ophthalmol. 2003;121:1738-1743.

ABSTRACT
Objective  To test the hypothesis that the kinetics of activation and deactivation of rod phototransduction are altered in children with Smith-Lemli-Optiz syndrome (SLOS), a common genetic disorder caused by an inborn error in cholesterol biosynthesis.

Methods  Thirteen patients with SLOS (median age, 4 years) were studied by means of scotopic full-field electroretinography. The kinetics of activation and deactivation of rod phototransduction were derived from the electroretinographic a-wave. Postreceptoral electroretinographic components were also evaluated.

Results  The kinetics of activation were below normal limits in all but 3 of the 13 patients. Rod cell recovery (deactivation) in SLOS was slower than normal in all 8 patients in whom it was studied. Postreceptoral sensitivity was below normal limits in all but 1 of the 13 patients.

Conclusions  The kinetics of phototransduction are slow in children with SLOS. This is likely a consequence of altered sterol composition in the cell membranes of the rod photoreceptors. To our knowledge, this is the first demonstration of altered kinetics of a membrane-bound signaling system in SLOS. Investigation of other membrane-bound signaling systems may be warranted in the quest to understand development and phenotype of individuals with SLOS.

INTRODUCTION

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PATIENTS WITH Smith-Lemli-Opitz syndrome (SLOS) (Online Mendelian Inheritance in Man [OMIM] 270400) have low serum cholesterol and detectable 7-dehydrocholesterol and 8-dehydrocholesterol concentrations due to a deficiency of the enzyme 7-dehydrocholesterol reductase.^1-6 The mechanisms by which the biochemical abnormalities cause the SLOS phenotype of microcephaly, mental retardation, facial dysmorphia, genital and limb abnormalities, poor growth, and failure to thrive remain unknown. Some SLOS-affected individuals have ptosis and cataracts.^7-8

Cholesterol, an important component of the lipid bilayer of cell membranes, affects the fluidity of membranes and the movement of proteins within the membranes.^9-12 Rhodopsin is the membrane-bound receptor in retinal rod cells.¹³ Cholesterol concentration seems to affect the folding and unfolding of rhodopsin in the outer segment disk membrane as it participates in the transduction cascade.¹¹ Regeneration of rhodopsin is less complete and slower in rod outer segment membranes with higher or lower cholesterol concentrations than found in control disc membranes.^9-12,14 Phototransduction is initiated by capture of photons by rhodopsin, which then diffuses in the disc membrane to activate transducin, which then activates phosphodiesterase resulting in involvement of cyclic guanosine monophosphate and closure of the channels in the plasma membrane.¹⁵ Deactivation proceeds through another series of molecular steps whereby the cell recovers the ability of the channels to close in response to light.¹⁵ The kinetics of the molecular processes involved in activation, and probably deactivation, are governed by the rate of encounter of the proteins involved in the transduction processes.¹⁶

The steps involved in visual transduction can be described precisely.^{15, 17-18} Furthermore, these processes can be investigated in patients using noninvasive electroretinographic (ERG) procedures.^19-21 We used contemporary ERG procedures to study the kinetics of activation and deactivation of phototransduction in rods of children with SLOS.

METHODS

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SUBJECTS

Data of 13 patients, including 3 sibling pairs (patients 2 and 3, 4 and 5, and 11 and 12), with biochemically confirmed SLOS are summarized in Table 1. At the ages studied, normal scotopic ERG response parameters are mature.¹⁹ Cholesterol precursors that are not present in healthy individuals were detectable in all of the SLOS-affected patients (Table 1). All patients received cholesterol supplementation, although compliance was inconsistent in some patients. The median spherical equivalent was +1.00 diopter (D) (range, -0.50 to +3.5 D). Patients 1 and 3 had tiny nuclear cataracts in both eyes. Patients 3, 11, and 12 had ptosis. The study conformed to the principles outlined by the Declaration of Helsinki and was approved by the Children's Hospital Committee on Clinical Investigation, Boston, Mass. Informed written consent was obtained from parents prior to the child's participation in the study. Healthy control subjects (n = 26) were aged 8 to 52 years (median age, 22 years).²⁰

View this table: [in this window] [in a new window] Table 1. Sterol Levels in Patients With Smith-Lemli-Opitz Syndrome

ERG PROCEDURES

Electroretinographic testing was done at the time of other investigations under light inhalation anesthesia that does not alter ERG responses.²² Procedures for preparation of the patient and data acquisition were performed as previously described.²⁰

Activation of Phototransduction in Rods

Rod photoresponse characteristics were estimated from the a-waves by means of the Hood and Birch²¹ formulation of the Lamb and Pugh^17-18 model of the biochemical processes involved in the activation of rod phototransduction. The main parameters of this model are S and R_mp3. Sometimes referred to as a sensitivity parameter,²¹ S summarizes the kinetics of the series of processes from photon capture up to, and including, closure of the channels in the plasma membrane of the photoreceptor.¹⁸ In other words, the molecular mobilities of the proteins in the transduction cascade are a determinant of S. R_mp3 is the amplitude of the saturated rod response²¹ and represents the number of channels available for closure by light. A curve-fitting routine (MATLAB, fimins subroutine; The MathWorks, Inc, Natick, Mass) was used to determine the best-fitting values of S, R_mp3, and t_d, a brief delay, in the following equation:
(1) (I,t) = {1 - exp[-0.5 I S (t-t_d)²]}R_mp3.
In this equation, I is the flash in estimated number of isomerizations per rod per flash. Approximately 8.5 isomerizations per rod per flash are produced by 1 scotopic troland second.²³ Fitting of the model was restricted to a maximum of 20 milliseconds after stimulus onset. For the 26 controls, the mean (SD) value of S is 10.15 (1.58) seconds^-2and that of R_mp3 is 391 (79) µV.

Deactivation of Phototransduction in Rods

The kinetics of recovery of the rod cell's response to light were evaluated using a paired flash paradigm^{20, 24-27} in 8 patients (patients 1-3, 8, and 10-13). Recovery, termed "deactivation," is accomplished by a series of molecular processes whereby the channel's and rod's circulating current are restored to a response-ready state.¹⁵ At 7 selected interstimulus intervals (2-120 seconds) after a test flash, a probe flash was presented. Between each test-probe pair, 2 minutes in the dark was allowed. The amplitude of the response to the probe was expressed as a percentage of amplitude of the response to the test flash alone. For 8 controls, amplitude is 50% when the median interstimulus interval is 3 seconds (range, 2-5 seconds) and 100% at the 120-second interstimulus interval.

Analysis of b-Waves

The b-wave stimulus-response data were fit by the function
(2) V/V_max = I/(I + )
as previously described.^{20, 28} The main parameters in this equation are V, the b-wave amplitude produced by flash intensity I; V_max, the saturated b-wave amplitude; and log , the flash intensity that evokes a half-maximum response amplitude. For controls, the mean (SD) value of log is -0.84 (0.10) log scotopic troland seconds and that of V_max is 378 (57) µV.

Analysis of P₂

In an analysis reminiscent of Granit,^29-30 the ERG waveform is considered the sum of the photoreceptor and postreceptoral retinal responses.^31-32 Equation 1 modeled the rod photoresponse, sometimes called "P₃." The photoresponse was digitally subtracted from the ERG waveform to obtain P₂, which is thought to represent mainly the on-bipolar cell response, but also activity in other second- and third-order retinal neurons.^31-36 In an analysis similar to that using equation 2 for the b-wave, the P₂ stimulus-response function was fit with
(3) P₂/P_2max = I/(I + k_p2),
where P_2max is the saturated amplitude and k_p2 is the semisaturation constant. Thus, 1/k_p2 is a measure of sensitivity.

STATISTICAL ANALYSIS

For each patient, data from 1 eye were analyzed. The patients' and controls' ERG parameters were compared (t test). In addition, individual patients' results were compared with the prediction interval for controls.³⁷

RESULTS

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Sample a- and b-wave records from 3-year-old patient 4 are shown in Figure 1. The mean values of the parameters calculated from the a-wave (S and R_mp3) and b-wave (log and V_max) were significantly lower in patients with SLOS (Table 2).

View larger version (43K): [in this window] [in a new window] Figure 1. A, Sample records from 3-year-old patient 4. B, Model fits to the a-wave (equation 1) and C, b-wave (equation 2) data. See the "Activation of Phototransuction in Rods" and the "Analysis of B Waves" subsections of the "Methods" section for equations 1 and 2, respectively.

View this table: [in this window] [in a new window] Table 2. Comparison of Responses in Patients With Smith-Lemli-Opitz Syndrome and Healthy Control Subjects*

The rod photoresponse parameters, R_mp3and S, for each patient are plotted in Figure 2. In every case of SLOS, S was below the normal mean value and most (10 of 13) were below the 95% prediction limit for normal (Figure 2A). Thus, the kinetics of the activation of phototransduction, represented by S, are slower than normal in patients with SLOS. As for R_mp3, only 1 (patient 3) has a value below the limits of normal (Figure 2B).

View larger version (30K): [in this window] [in a new window] Figure 2. Rod photoresponse parameters, S (the sensitivity parameter) and Rmp3(the amplitude of the saturated rod response and represents the number of channels in the plasma membrane of the photoreceptor), representing the activation of rod phototransduction in 13 patients with Smith-Lemli-Opitz syndrome (SLOS) and 26 healthy control subjects. The upper and lower limits of the 95th and 99th prediction intervals and the normal means are as indicated. PL indicates the upper and lower limits of the 95th and 99th prediction intervals.

Results of the paired flash test of deactivation are shown in Figure 3. With decreasing time after the test flash, as the sample records for patient 2 illustrate (Figure 3A), the amplitude of the response to the probe flash decreased. In every patient, the interstimulus interval (Figure 3B) at which the response was 50% of the dark-adapted response amplitude was longer (range, 6-16 seconds; median, 10.5 seconds) than in any control subject (range, 2-5 seconds; median, 3 seconds). Thus, the kinetics of deactivation were significantly delayed in the patients (Table 2). ^{15, 24, 26-27}

View larger version (28K): [in this window] [in a new window] Figure 3. Results of the paired flash test. A, The a-wave responses of patient 2 to the test and probe flashes at indicated interstimulus intervals. B, The patients' with Smith-Lemli-Opitz syndrome (SLOS) results (n = 8) compared with the mean responses of the healthy control subjects (n = 8). The interstimulus interval at which the response to the probe flash was 50% of the amplitude of the response to the test flash alone was longer in the patients with SLOS than in the healthy control subjects.

Sample P₂records are shown in Figure 4A. The parameters of the P₂ stimulus-response function, P_2maxand log k_p2, calculated by the fit of equation 3 to the P₂ stimulus-response data (Figure 4B), are shown in Figure 4C and D. All but patient 6 had log k_p2 values below the 95% prediction limit of normal, whereas only 4 had P_2max below the 95% prediction limit. The patients' mean values of log k_p2 and P_2max differ significantly from those of the controls (Table 2).

View larger version (35K): [in this window] [in a new window] Figure 4. Summary of P2 analysis and results. A, The family of P2 waves for patient 12 is shown. B, P2stimulus-response function was plotted from the data in 4A. C, Log kp2 (the semisaturation constant) is shown for patients with Smith-Lemli-Opitz syndrome (SLOS) and healthy control subjects. D, P2max (the saturated amplitude) is shown for patients with SLOS and healthy controls with the mean level marked. PL indicates the upper and lower limits of the 95th and 99th prediction intervals.

Receptoral and postreceptoral deficits in SLOS sensitivity (S and log k_p2) and saturated amplitude (R_mp3 and P_2max) were compared and the results are shown in Figure 5. For both sensitivity and saturated amplitude, receptoral and postreceptoral deficits are correlated (sensitivity, r = 0.64, P = .02; saturated amplitude, r = 0.78, P = .003, respectively). Deficits appear more marked in postreceptoral than receptoral sensitivity (Figure 5A). Deficits in receptoral and postreceptoral saturated amplitudes are minimal (Figure 5B). Low sensitivity at the receptor can cause low postreceptoral sensitivity with little change in saturated amplitude.^31-32,38

View larger version (32K): [in this window] [in a new window] Figure 5. Receptoral and postreceptoral deficits in sensitivity (A) and in saturated amplitude (B) are compared. Solid circles, represent patients with Smith-Lemli-Opitz syndrome (SLOS); open circles, the healthy control subjects; dashed lines, the range of values in healthy control subjects.

None of the ERG parameters (Table 2) was correlated with the concentrations of cholesterol, 7-dehyrocholesterol, 8-dehydrocholesterol, or with the ratio of cholesterol to total sterol levels (Table 1). The ERG parameters of the 4 patients with cholesterol concentrations less than 100 mg/dL did not differ significantly from those of the other 9 patients. None of the ERG parameters varied with age.

COMMENT

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The kinetics of rod activation (Figure 2) and deactivation (Figure 3) are slowed significantly in these children with SLOS. The mean value of S, which summarizes the kinetics of the proteins involved in the activation of phototransduction, is only 61% of normal. Possibly the basis for the slow kinetics, as in the experimental cell membranes,^{11, 14} is a low cholesterol concentration in the outer segment membranes. The retina of the rat model of SLOS has a low cholesterol concentration.⁹

Although statistically lower in SLOS-affected patients than in controls, the saturated amplitude of the rod response, R_mp3, is robust at 84% of normal. Thus, the number of channels available for closure by light and length of the outer segment must not be reduced drastically in SLOS-affected patients. A small decrease in the outer segment length and a consequent decrease in the level of rhodopsin available for photon capture are unlikely to explain the proportionately larger decrease in S. Disorder in the cholesterol-deficient lipid bilayer and impaired mobility of proteins in the outer segment membranes are 2 possible, nonmutually exclusive explanations for low S.

None of the sterol levels (Table 1) were correlated with any ERG parameter. Plasma cholesterol level accounts for only 33% of the overall severity score in patients with SLOS.³⁹ Furthermore, as does the brain, the retina makes its own cholesterol by the same biosynthetic pathway as in other tissues. Accordingly, cholesterol levels in peripheral blood are not necessarily an indicator of cholesterol levels in the retina. As in the rat model of SLOS, the deficit in the cholesterol concentration in the retina may not be as severe as in the serum.⁹

The slow kinetics in SLOS are evidence of significant impairment of a membrane-bound signaling system, namely, rhodopsin in the rod outer segment membranes. Whether the retinal dysfunction is progressive or is associated with visual impairment is not yet known. For now, we recommend that the vision and retinal status of children with SLOS be monitored. In the quest to learn more about SLOS, investigation of other membrane-bound signaling systems involved in development^40-41 and neural processes may be warranted.

AUTHOR INFORMATION

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Corresponding author: Anne B. Fulton, MD, 300 Longwood Ave, Boston, MA 02115 (e-mail: anne.fulton{at}tch.harvard.edu).

Submitted for publication November 19, 2002; final revision received May 23, 2003; accepted June 20, 2003.

This study was supported in part by grants EY 10597 (Drs Hansen and Fulton) and M01 RR02172 to Children's Hospital, Boston, from the National Eye Institute, National Institutes of Health, Bethesda, Md.

From the Coordinated Care Service (Dr Elias) and the Departments of Ophthalmology (Drs Hansen and Fulton) and Medicine (Genetics) (Dr Irons), Children's Hospital, and the Department of Specialty and Advanced Care, New England College of Optometry (Dr Quinn), Boston, Mass. Dr Elias is now with the Division of Pediatrics and Genetics, Children's Hospital, Denver Colo. The authors have no relevant financial interest in this article.

REFERENCES

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