April 2011
Volume 52, Issue 5
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Eye Movements, Strabismus, Amblyopia and Neuro-ophthalmology  |   April 2011
Clinical and Oculomotor Characteristics of Albinism Compared to FRMD7 Associated Infantile Nystagmus
Author Affiliations & Notes
  • Anil Kumar
    From the Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Leicester Royal Infirmary, Leicester, United Kingdom.
  • Irene Gottlob
    From the Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Leicester Royal Infirmary, Leicester, United Kingdom.
  • Rebecca J. Mclean
    From the Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Leicester Royal Infirmary, Leicester, United Kingdom.
  • Shery Thomas
    From the Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Leicester Royal Infirmary, Leicester, United Kingdom.
  • Mervyn G. Thomas
    From the Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Leicester Royal Infirmary, Leicester, United Kingdom.
  • Frank A. Proudlock
    From the Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Leicester Royal Infirmary, Leicester, United Kingdom.
  • Corresponding author: Frank A. Proudlock, Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, P.O. Box 65, Leicester, LE2 7LX, UK; fap1@le.ac.uk
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 2306-2313. doi:10.1167/iovs.10-5685
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      Anil Kumar, Irene Gottlob, Rebecca J. Mclean, Shery Thomas, Mervyn G. Thomas, Frank A. Proudlock; Clinical and Oculomotor Characteristics of Albinism Compared to FRMD7 Associated Infantile Nystagmus. Invest. Ophthalmol. Vis. Sci. 2011;52(5):2306-2313. doi: 10.1167/iovs.10-5685.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: Previous studies have found no difference between nystagmus characteristics associated with idiopathic infantile nystagmus (IIN) and that associated with albinism. The present aim is to compare the oculomotor characteristics and other associated clinical features of albinism and a genetically homogenous group of IIN volunteers where the nystagmus is associated with FRMD7 mutations.

Methods.: Oculomotor characteristics and related clinical features between albinism (n = 52) and idiopathic nystagmus associated with FRMD7 mutations (FRMD7-IIN, n = 83) were compared. The nystagmus characteristics compared included amplitude, frequency, intensity of nystagmus, foveation characteristics, and waveform type. Other clinical features compared were strabismus, stereopsis and anomalous head posture.

Results.: The FRMD7-IIN group contained a higher proportion of pendular waveform types compared with the albinism group (P < 0.0001). Nystagmus frequency was significantly lower in albinos (mean = 3.3 Hz, SD = 0.13 Hz) compared with the FRMD7-IIN group (mean = 4.3Hz, SD = 0.18 Hz) (F = 14.5, P < 0.0001). Strabismus and anomalous head posture was seen in higher proportions in the albinism group, and stereopsis was worse compared with the FRMD7-IIN group (P ≪ 0.0001).

Conclusions.: Differences in nystagmus characteristics associated with albinism and those associated with FRMD7 mutations leading to IIN are described for the first-time. These findings may provide useful information in the future elucidation of mechanisms underlying the nystagmus associated with albinism and idiopathic infantile nystagmus.

Albinism is a group of inherited disorders of melanin metabolism. It is broadly divided into oculocutaneous albinism, characterized by hypopigmentation of the skin, hair, and eyes, and ocular albinism, involving only the eyes. The ocular features associated with albinism are infantile nystagmus, iris transillumination defects, high refractive error, strabismus, fundal hypopigmentation, foveal hypoplasia, and an abnormal axonal crossing pattern at the optic chiasm. Albinism exhibits a large degree of phenotypical heterogeneity thus making diagnosis difficult. 
Previous studies exploring the association between motor and sensory characteristics of infantile nystagmus, 1,2 did not find any differences between the different groups of infantile nystagmus such as albinism and idiopathic infantile nystagmus (IIN). Nystagmus was found to be bilateral, conjugate, and horizontal, with the waveform showing accelerating slow phases in both IIN and albinism groups. These observations might implicate a common mechanism behind these nystagmus forms. 
A classification of nystagmus, based on the time of onset of nystagmus and the accelerating slow waveforms seen on eye movement recordings, have grouped all infantile nystagmus types into one category, namely, infantile nystagmus syndrome. 3 There would be considerable value in identifying features of nystagmus that would suggest the presence of albinism for the purposes of advising on visual prognosis, genetic counseling, and the need for proper skin protection. 
In the Leicestershire Nystagmus Survey, recently performed in the United Kingdom, Sarvananthan et al. 4 found that nystagmus associated with albinism and nystagmus without associated sensory defects (i.e., IIN) were the two most common categories of infantile nystagmus, with an incidence of 2.5 per 10,000 and 2.9 per 10,000, respectively. 
In 2006, we found a gene, called FRMD7, causing X-linked IIN, 5 and subsequently Thomas et al. 6 compared the phenotypical characteristics between patients with and without mutations in this gene. Good visual acuity, normal ocular alignment, and good binocular vision were found in both groups of patients. However, anomalous head posture was significantly less in patients with mutations in the FRMD7 gene compared with the group without mutations. This reflected the reduced nystagmus amplitude at primary position in the group with FRMD7 gene mutations, associated with more central null regions in this group. 
The discovery of a gene for IIN permits us to compare for the first time, the oculomotor characteristics associated with albinism to those associated with a genetically homogenous group of IIN patients, that is, with FRMD7 mutations (FRMD7-IIN). We have also used a large sample of carefully diagnosed albinism volunteers (n = 52), representative of the large phenotypic variation evident in this group. The oculomotor characteristics and other relevant clinical features we have compared are strabismus and stereopsis, anomalous head posture nystagmus waveform, and nystagmus amplitude, frequency, and foveation characteristics. 
Methods
Volunteers
Fifty-two albinotic subjects (mean age, 36 years; range, 17–67 years) were recruited along with 83 subjects (mean age, 36 years; range, 3–88 years) who were clinically diagnosed with IIN and subsequently found to have mutations in the FRMD7 gene. 5 The study fulfilled the tenets of the Declaration of Helsinki and was approved by the local ethics committee. Written informed consent was obtained from all subjects. 
Diagnosis of Albinism and FRMD7-Associated IIN
Detailed ophthalmological examination was performed on all subjects including slit lamp biomicroscopy in the dark to identify iris transillumination defects. Electrodiagnostics were performed on all the subjects according to the ISCEV standards, including both electroretinography (ERG) and visual evoked potential (VEP). ERG was performed to rule out any retinal pathology causing nystagmus, and all subjects with ERG abnormalities were excluded from the study. Multichannel VEP was performed in all the subjects, and asymmetry of hemispheric responses on monocular stimulation was used as to indicate chiasmal misrouting. 
Albino volunteers exhibited a wide range of phenotypical characteristics, ranging from a physically normal appearance to obvious features such as hypopigmentation of skin and hair. Diagnosis of albinism was confirmed by the coexistence of three signs: 1) presence of asymmetric hemispheric VEP responses on monocular stimulation, 2) macular hypoplasia confirmed by either fundus examination or optical coherence tomography, and 3) iris transillumination (Summers classification: grades 1–4 7 ). IIN subjects had a normal ERG, and no asymmetry was seen on VEP. All the subjects had X-linked mode of inheritance with mutations in the FRMD7 gene. 5  
Eye Movement Recordings
Horizontal and vertical eye movement recordings were recorded at 250 Hz using a pupil tracker (Eye Link I; SensoMotoric Instruments, Berlin, Germany). Data from each eye was calibrated separately offline by selecting foveation periods when fixating targets at ±15° eccentricity, horizontally and vertically, and primary position (0°). The primary analysis was performed on sections of data (minimum 3 seconds) when the volunteers were attempting to maintain fixation at primary position and targets at ±15° eccentricity, horizontally. The amplitude and frequency of nystagmus were defined from peak-to-peak excursions of the fundamental oscillation (determined from adaptive smoothing of the data). Waveforms were characterized based on the 12 waveforms described by Dell'Osso and Daroff. 8 The predominant waveform seen in the recording was taken as a primary waveform. Extended nystagmus visual acuity (NAFX), which predicts the visual acuity based on the foveations seen on eye movement recordings, was calculated for both primary position and ±15° gaze positions using scripts developed by Jacobs and Dell'Osso (www.omlab.org). Since all nystagmus in both albinos and FRMD7-IIN was conjugate, only the data for the right eye were used in the analysis. The vertical component of the nystagmus was estimated as the vertical amplitude/horizontal amplitude × 100%. Periodic alternating nystagmus (PAN) was identified from prolonged periods of recording (>7 minutes) when the eyes were fixating a target at primary position (0°). Although difficult to characterize definitively because of the underlying nystagmus as well as possible PAN, manifest latent nystagmus (MLN) was identified from monocular occlusion of either eye and the slow-phase velocity characteristics. MLN was defined as that leading to a change in the beating direction of the nystagmus on monocular occlusion, with the beating direction always toward the open eye in combination with the presence of decreasing velocity or linear slow phases. Changes in nystagmus waveform (e.g., change in beating pattern, intensity, or the velocity characteristics of the slow phase) caused by monocular occlusion were also noted. Care was taken to distinguish changes in nystagmus after occlusion caused by a shift in gaze due to strabismus. 
On a subset of patients, without periodic alternating nystagmus, a characterization of the null region was performed. This involved participants following a fixation target (1° diameter) moving every 8 seconds horizontally from −24° to +24° in 3-degree steps (5 FRMD7-IIN volunteers and 17 volunteers with albinism). The location and eccentricity of the null region was estimated along with the amplitude, frequency, intensity, NAFX, and waveform of the nystagmus at the null region. 
Clinical Tests
Visual acuity was measured using Snellen visual acuity charts for distance at 6 meters and converted to logMAR for subsequent analysis. Anomalous head posture (AHP) was measured while volunteers read a distance visual acuity chart. The AHP was classified into three categories (minimal AHP, i.e., <5° of head turn; moderate AHP with 5–15° of head turn; and large AHP with >15° of head turn). Strabismus was detected with corneal light reflex testing and measured with alternating prism cover test (used for statistical analysis). Stereopsis was tested using the Lang test. 
Statistics
Categorical variables were compared using the Pearson χ2 test (used for stereopsis, strabismus, and waveform) and the gamma statistic (used for anomalous head posture). Since the majority of the eye movement data were not normally distributed (as confirmed by the Shapiro-Wilk test), amplitude, frequency, intensity, and NAFX values were log transformed leading to a closer approximation to normality. This enabled linear mixed models (two-way repeated measures ANOVA) to be applied allowing the inclusion of paired (i.e., eccentricity) and unpaired factors (albinotic versus FRMD7 associated) in the model and exploration of interactions between terms. Visual acuities were compared using a Mann-Whitney test. 
Results
Nystagmus Characteristics
Figure 1 shows original eye movements of two volunteers with albinism (one with PAN) and one volunteer from the FRMD7-IIN group. Jerk-related waveforms are seen in the first albinism subjects in all three gaze positions and in two positions of gaze (−15° and +15°) in the second volunteer. A fine pendular nystagmus is present in primary position (0°) for the second albino volunteer. Pendular and pendular-related waveforms are more clearly seen in the FRMD7-IIN volunteers with a superimposed jerk component also being present in more eccentric gaze positions. 
Figure 1.
 
Original eye movement data in primary position (0°) and 15° to right (+15°) and left (−15°) for (A) an albino volunteer and (B) an FRMD7-IIN subject. (C) Right beating, left beating, and quiet phases are shown for an albinism volunteer with periodic alternating nystagmus.
Figure 1.
 
Original eye movement data in primary position (0°) and 15° to right (+15°) and left (−15°) for (A) an albino volunteer and (B) an FRMD7-IIN subject. (C) Right beating, left beating, and quiet phases are shown for an albinism volunteer with periodic alternating nystagmus.
Plane of Nystagmus and Waveform.
All volunteers in the albino and FRMD7-IIN group had conjugate nystagmus that was primarily horizontal in direction. A small vertical component to the nystagmus was present in both groups (albino group: median = 3.10%, interquartile range = 4.53%; FRMD7-IIN group: median = 6.28%, interquartile range = 4.88%). The vertical component was significantly higher in the FRMD7-IIN group (Mann-Whitney test, P = 0.014). 
Nystagmus waveforms (excluding PAN) were classified into the 12 categories of pendular, jerk, and bidirectional waveforms described by Daroff and Del'Osso 8 and are represented in Figure 2 banded according to visual acuity. The overall proportion of pendular, jerk, and bidirectional nystagmus was 25.7%, 66.7%, and 7.6% in the albinism group and 42.7%, 42.7%, and 14.5% in the FRMD7-IIN group, respectively. The FRMD7-IIN group contained a higher proportion of all three types of pendular waveform types compared with the albinism group, whereas higher proportions of all four types of jerk nystagmus were evident in the albinism group (Pearson χ2 test, P < 0.0001). Pure jerk waveforms (J) were associated with poor visual acuity (≥0.7) in the albinism group (e.g., see Fig. 2A at +15°). Although these exhibited minimal foveation periods, unlike vestibular and optokinetic jerk waveforms, a brief acceleration in the slow phase immediately after the quick phase was evident. 
Figure 2.
 
The proportion of waveform types from the classification given by Dell'Osso and Daroff 8 for the albino and the FRMD7 group. A greater proportion of pendular waveforms were observed in the FRMD7 group compared with albinism volunteers.
Figure 2.
 
The proportion of waveform types from the classification given by Dell'Osso and Daroff 8 for the albino and the FRMD7 group. A greater proportion of pendular waveforms were observed in the FRMD7 group compared with albinism volunteers.
Periodic alternating nystagmus was observed in 29.4% of individuals in the albinism group and 23.5% of the FRMD7-IIN group. Nystagmus waveforms associated with PAN for both groups were either jerk related (80% in albinism and 75% in FRMD7-IIN; mainly jerk-extended foveation or pseudocycloid) or dual-jerk waveforms (20% in albinism and 25% in FRMD7-IIN) during active phases. During the quiet phase the most commonly encountered oculomotor patterns were no significant oscillation (66.7% in albinism and 50% in FRMD7-IIN), followed by pendular waveforms (33.3% in albinism and 41.7% in FRMD7-IIN). 
Manifest latent nystagmus, defined as that which led to a change in the beating direction of the nystagmus, with the beating direction always toward the open eye in combination with the presence of decreasing velocity or linear slow, was identified in 8 of the 52 albino volunteers (15.4%) and none of the 51 volunteers in the FRMD7-IIN group. Fourteen albino volunteers and 7 FRMD7-IIN volunteers also showed a change in nystagmus waveform, that is, a change in the quick phase beating direction, intensity, or slow-phase velocity characteristics with monocular occlusion of either eye. The presence of MLN without infantile nystagmus waveforms was detected in one individual with albinism where the nystagmus during binocular viewing (which was much smaller than during monocular viewing) had slow phases that were always decelerating. 
Amplitude, Frequency, Intensity, and Foveation of Nystagmus.
The amplitude, frequency, intensity, and foveation characteristics (measured using the extended nystagmus acuity function [NAFX]) of the nystagmus for patients without PAN in left gaze (−15°), primary position (0°), and right gaze (+15°) for subjects in both the groups is shown in Figure 3 (log values displayed for amplitude, frequency, and intensity and logMAR for NAFX). Linear mixed models were used to show that there was no significant effect of group (albino versus FRMD7-IIN, F = 2.87, P = 0.092) or eccentricity (F = 2.03, P = 0.13) on nystagmus amplitude. In contrast, the difference in nystagmus frequency between albino and FRMD7-IIN groups was highly significant (F = 42.2, P < 0.0001) with a significant effect of eccentricity (F = 3.18, P = 0.044). The mean frequency was 3.20 Hz (SD 0.99 Hz) in albinos and 4.18 Hz (SD 1.29 Hz) in the FRMD7-IIN group. For nystagmus intensity there was no significant effect for group (F = 1.16, P = 0.28), although there was for eccentricity (F = 3.85, P = 0.023). For NAFX there was a significant effect for both group (F = 4.47, P = 0.036) and eccentricity (F = 5.06, P = 0.007). Figure 4 represents the use of frequency of nystagmus as a parameter to distinguish between nystagmus associated with albinism and FRMD7-IIN. 
Figure 3.
 
Means (error bars represent SEM) of (A) amplitude (log values), (B) frequency (log values), (C) intensity (log values), and (D) extended nystagmus acuity function (NAFX in logMAR) are shown during attempts to hold left (−15°) central (0°) and right gaze (+15°) for albinos and FRMD7-IIN volunteers.
Figure 3.
 
Means (error bars represent SEM) of (A) amplitude (log values), (B) frequency (log values), (C) intensity (log values), and (D) extended nystagmus acuity function (NAFX in logMAR) are shown during attempts to hold left (−15°) central (0°) and right gaze (+15°) for albinos and FRMD7-IIN volunteers.
Figure 4.
 
The probability that given a certain frequency of nystagmus for an individual taken at random from the whole data set that the nystagmus will be associated with albinism or FRMD7-IIN. The numbers shown next to the symbols indicate the percent of the whole group each point represents.
Figure 4.
 
The probability that given a certain frequency of nystagmus for an individual taken at random from the whole data set that the nystagmus will be associated with albinism or FRMD7-IIN. The numbers shown next to the symbols indicate the percent of the whole group each point represents.
No significant differences (P > 0.05) were observed between the FRMD7-IIN and albinism groups with respect to the null region location (medians: FRMD7-IIN, −3.0°; albinism, 3.0°) and eccentricity (medians: FRMD7-IIN, 3.0°; albinism, 6.0°), or amplitude (means: FRMD7-IIN, 1.6°; albinism, 2.7°), frequency (means: FRMD7-IIN, 3.0 Hz; albinism, 2.8 Hz), intensity (means: FRMD7-IIN, 6.5°/s; albinism, 8.4°/s) and NAFX (means: FRMD7-IIN, 0.41; albinism, 0.55 logMAR equiv.) at the null region. The waveform of the nystagmus at the null region was mostly pendular related in the FRMD7-IIN group (pendular with foveating saccades = 3; pendular = 1; jerk = 1) and either jerk-related or with minimal nystagmus due to a very slow drift in the albinism group (jerk extended foveation = 2; bidirectional jerk = 4; very slow drift = 7; pendular = 4). 
Clinical Features
Visual Acuity.
The median logMAR visual acuity was significantly higher in albinos (median, 0.50; quartiles, 0.46–0.73) compared with the FRMD7-IIN group (median, 0.176; quartiles, 0.097–0.301) (Mann-Whitney, Z = −8.164, P ≪ 0.0001; Fig. 5). 
Figure 5.
 
Visual acuity (converted to logMAR) in albinos and IIN associated with FRMD7 mutations (FRMD7-IIN).
Figure 5.
 
Visual acuity (converted to logMAR) in albinos and IIN associated with FRMD7 mutations (FRMD7-IIN).
Strabismus and Stereopsis.
Strabismus was detected in 71.2% (n = 37) of albino subjects, of which 27 were esotropes and 10 exotropes (Fig. 6A). In contrast, strabismus was significantly lower in FRMD7 associated with IIN (FRMD7-IIN, P ≪ 0.0001) being present in only 7.8% (n = 7) of volunteers (three esotropes, three exotropes, and one hypertrope). Likewise fewer albinos demonstrated stereopsis (Fig. 6B), tested using the Lang test (negative in 80.8%), compared with the FRMD7-IIN group (negative in 6.6%, P ≪ 0.0001). 
Figure 6.
 
Comparisons of the percentage of (A) strabismus, (B) stereopsis, and (C) degree of anomalous head posture between albinos and IIN associated with FRMD7 mutations (FRMD7).
Figure 6.
 
Comparisons of the percentage of (A) strabismus, (B) stereopsis, and (C) degree of anomalous head posture between albinos and IIN associated with FRMD7 mutations (FRMD7).
Anomalous Head Posture.
Anomalous head posture (AHP) was recorded in 47 volunteers of the albinism group and 80 volunteers in the FRMD7-IIN group (Fig. 6C). AHP of greater than 5° was present in over half of albino volunteers compared with only 15% of the FRMD7-IIN group (P ≪ 0.0001). Interestingly, 15% of the albinism group had AHP of >15° compared with none in the FRMD7-IIN group. 
Discussion
We describe, for the first time, differences in nystagmus characteristics between a group of patients with albinism and a group with IIN associated with FRMD7 mutations. We also confirm the existence of a number of other abnormalities, namely, the presence of strabismus contributing to absent stereopsis, large anomalous head posture, and reduced visual acuity. 
All the 12 waveforms described by Dell'Osso and Daroff 8 were seen in our subject population. However, we found a higher proportion of pendular waveform types in the FRMD7-IIN group compared with more jerk waveforms seen in the albino group. This stands in contrast to that observed by Abadi and Bjerre 1 who did not find any particular waveform specific to either IIN or albinism. Given that there are no obvious direct sensory deficits associated with the FRMD7-IIN except those indirectly caused by the nystagmus itself, it is interesting that more pendular nystagmus is associated with nystagmus that occurred in the absence of any identifiable sensory deficit. This contradicts the commonly accepted notion that so-called “motor” nystagmus is jerk and “sensory” nystagmus is pendular. 
We noted that the frequency of nystagmus was significantly less in the albinism group (mean, 3.3 Hz), in all three positions of gaze, compared with the IIN group (mean, 4.3 Hz), and that the difference was highly significant (P < 0.0001). We also observed lower nystagmus frequency and slightly better foveation characteristics for the albino group in comparison with the FRMD7-IIN group. This implies that the major determinant of the reduced visual acuity observed in the albino group is due to sensory abnormalities, although it is not clear as yet how foveal hypoplasia relates to visual acuity. 9 This also suggests that foveation may still be useful even in the absence of a normal fovea. Abadi and Dickinson 10 in a study of waveform characteristics in infantile nystagmus found that the waveform shape and precision of foveations to be better indices of visual acuity than intensity of nystagmus. This has led to the development of the extended nystagmus acuity function, which estimates visual acuity based on the foveation characteristics. 11  
A number of oculomotor features were also similar between the two groups. These included the presence of a primarily horizontal nystagmus in all cases observed, although both groups had a small vertical component that was larger in the IIN group. In addition, a significant proportion of periodic alternating nystagmus (PAN) occurred in both groups (29.4% of individuals in the albinism group and 23.5% in the FRMD7-IIN group). The PAN observed in the two groups had similar characteristics. These were in accord with that previously described by Abadi and Pascal 12 in albino patients. There were no significant differences in null region characteristics between the two groups, although the sample size was too small to provide any conclusive evidence. 
MLN was defined as that which led to a change in the beating direction of the nystagmus on monocular occlusion (with the beating direction always toward the open eye) in combination with the presence of decreasing velocity or linear slow phases. MLN defined using these criteria was only observed in the albino patients and was associated with the higher prevalence of strabismus in this group. A number of patients (14 albino and 7 FRMD7-IIN) did not demonstrate this specific combination but showed a change in nystagmus waveform (e.g., change in beating pattern, intensity, or the velocity characteristics of the slow phase) under monocular occlusion. It is possible that these patients were demonstrating a latent component of MLN that was interacting with the nystagmus waveform associated with infantile nystagmus syndrome. Manifest latent/latent nystagmus is likely to be a single entity since most patients with clinical latent nystagmus show a small spontaneous jerk nystagmus on eye movement recordings with both eyes viewing. 13 It is likely that there may also be a manifest component in these patients that is masked by the waveform associated with the infantile nystagmus syndrome. 
The mechanism(s) behind infantile nystagmus are poorly understood. Numerous models have been developed that generate common waveforms associated with infantile nystagmus, most of which include abnormal circuitry of the slow eye movement and gaze-holding systems. 14 Optican and Zee 15 modeled IN on an unstable neural integrator due to a reversal of the velocity feedback loop leading to accelerating (exponential) slow phases. Jacobs and Dell'Osso 16 suggest that, rather than abnormal neural integrator feedback loops, IN waveforms are caused by an abnormality in the feedback loop internal to the smooth pursuit subsystem leading to sinusoidal oscillations. These are shaped by the interposition of braking and foveating saccades. Based on time series analysis, Akman et al. 17 also suggest that the origin of jerk waveforms is in unstable circuitry that lies before the neural integrator. However, they suggest that a model of the saccadic system based on nonlinear dynamics is able to produce all the jerk, bidirectional jerk, and pendular nystagmus waveforms associated with IN. 18 In contrast to models that introduce abnormalities in oculomotor circuitry, Harris and Berry 19 have proposed that IN may be caused by plasticity in the normal oculomotor system during periods of early visual deprivation. They suggest that if the normal visual system is deprived of high-spatial frequency contrast stimulation during visual development, then oscillations develop to improve the contrast sensitivity to stimuli of lower spatial frequency. It is also possible that different mechanisms underlie jerk nystagmus, which is usually gaze dependent, and pendular nystagmus, which is less gaze dependent, although frequently these waveforms coexist in the same individual. 
It is not clear at this point if the differences we observed in nystagmus waveforms are due to a common mechanism behind the nystagmus in the two groups being affected differentially by associated deficits in albinism, such as foveal hypoplasia and/or MLN. The similarities observed in the nystagmus in the two groups might suggest this. Alternatively, different mechanisms could underlie nystagmus associated with albinism and that associated with FRMD7-IIN, although more evidence is required to substantiate this. 
Because of the phenotypical heterogeneity the diagnosis of albinism is not always straightforward. Charles et al. 20 reported 20% of affected males with nystagmus from U.K. pedigrees had previously been misdiagnosed as IIN. According to Shiono et al. 21 70% of Japanese patients with X-linked ocular albinism were misdiagnosed as having IIN with or without macular hypoplasia. King et al. 22 described the clinical characteristics of seven patients with oculocutaneous albinism who were previously diagnosed as having unassociated infantile nystagmus syndrome or disorders of retina other than albinism. Genetic testing can help in definitive diagnosis of these conditions, but it is not performed routinely. In addition, a recent study by Hutton and Spritz 23 found that mutations cannot be located for known ocular albinism genes for 24% of patients in a Caucasian population. 
In this study we had the opportunity for the first time of using a genetically homogeneous group of patients with FRMD7 mutations avoiding the possibility of patients with albinism being misdiagnosed with IIN. The diagnosis of albinism in this study was made based on the coexistence of the clinical features of iris transillumination defects, macular hypoplasia, optic nerve misrouting at the chiasm detected using multichannel VEP, and nystagmus. Although this is likely to give a better diagnostic success rate than genetic testing because of the presence of a significant level of undetected mutations in the albino population, some difficulties are still associated with using these criteria. Both VEP asymmetry and macular hypoplasia as diagnostic signs have been described in the literature as rarely being definitive for albinism. For example, foveal hypoplasia and chiasmal misrouting have also been reported in patients suspected as nonalbinotic who had nystagmus, no iris transillumination defect, and normal fundal pigmentation. 24 Ung et al. 25 reported optic nerve misrouting recorded on pattern onset VEP recording in 15% of their patients diagnosed with congenital stationary night blindness (CSNB). Tremblay et al. 26 also reported crossed VEP asymmetry in 9 of 10 patients diagnosed with CSNB2. However, all our patients fulfilled four clinical criteria (abnormal VEP crossing, macular hypoplasia, iris transillumination, and nystagmus) that strongly support the diagnosis of albinism. 
In our study we found strabismus to be present in high proportions in albinism subjects (71.2%) and low proportions in FRMD7-IIN group (7.8%). Both findings are at variance with numerous previous reports, although estimates of the prevalence of strabismus in subjects with infantile nystagmus vary widely (see Table 1). Brodsky and Fray 27 found the incidence of strabismus to be 53% in albinos compared with 17% of IIN subjects. Abadi and Dickinson 10 found strabismus in 90.5% of albinos compared with 37.1% in subjects with infantile nystagmus due to various other causes including IIN. Gradstein et al. 28 found strabismus in 74% of subjects with Hermansky-Pudlack syndrome, a form of oculocutaneous albinism. The prevalence of strabismus found in patients with FRMD7 mutation was 7.8% 6 and 44%. 30 Strabismus was seen in 36% of autosomal dominant IIN patients. The high prevalence of strabismus seen in the albinism group we used could be explained by the large clearly defined cohort sample. The prevalence of strabismus seen in albinism subjects is attributed to the cortical, callosal, and chiasmal misrouting seen in these subjects. 30 Thomas et al. 6 also found the incidence of strabismus to be similar (10%) in IIN not associated with FRMD7 mutations compared with FRMD7-IIN. 
Table 1.
 
Comparison of Clinical Findings to Previous Studies
Table 1.
 
Comparison of Clinical Findings to Previous Studies
Study Albinism IIN
logMAR Visual Acuity Strabismus (%) Stereopsis (%) AHP (%) logMAR Visual Acuity Strabismus (%) Stereopsis (%) AHP (%)
Abadi and Dickinson 10 0.4 to 1.0 90.5 4.0 −0.1 to 1.0
Brodsky and Fray 27 53.3 16.7
Gradstein et al. 28 * 0.0 to 1.2 74.1 40.0 63.0
Kerrison et al. 29 0.2 to 0.7 35.7
Self et al. 30 0.1 to 0.5 44.0
Present study† ‡ 0.2 to 1.0 71.2 19.2 51.1 −0.2 to 0.8 7.8 93.4 15.0
In our study we found 19.2% (n = 10) of subjects in the albinism group were Lang positive, which suggests presence of stereopsis in this group. Other studies have also reported the presence of clinically detectable stereopsis in subjects with albinism. 32 34 The exact neural mechanism by which subjects with albinism demonstrate stereopsis is not known. Various studies suggest that the compensatory restructuring of corpus callosal projections could facilitate binocular disparate information in albino subjects. 33,35,36 The majority of subjects in the FRMD7-IIN group had good stereopsis. Subjects with poor stereopsis had strabismus, which could explain the probable association of fusional maldevelopment in these subjects. 
Anomalous head posture is associated with an eccentrically located null region. AHP is used to reduce the intensity of nystagmus to achieve optimal vision. It has been postulated that patients with albinism may not benefit from using AHP because of their associated foveal hypoplasia. 37 However, we found AHP in 47 of 52 patients (90.4%) with albinism indicating that optimization of patients with lower visual acuity may still offer considerable benefit. Previous studies have also shown AHPs to be less frequent in albinos compared with other congenital nystagmus groups. 12,38 In a study on the clinical features of infantile nystagmus in the first 6 months of life, Stevens and Hertle 39 reported AHP in 19% of patients. Abadi and Whittle 40 found AHP in 53% (9 of 16 subjects) subjects, which included both IIN and albino subjects. The adoption of head posture was not linked to either albinism or IIN or ocular anomaly group in their study. Stevens and Hertle 39 found that the presence of AHP correlated with good vision in infantile nystagmus. In contrast with this we found AHP in higher proportions in the albino group compared with the FRMD7- IIN group, although visual acuity was much better in the FRMD7- IIN group. 
In conclusion, we have described for the first time differences in nystagmus characteristics between a group of patients with albinism and a group with IIN associated with FRMD7 mutations, namely, reduced frequency and higher proportions of jerk waveforms in albinism. Although these findings are likely to provide little diagnostic benefit, clinically these observations may assist in the future elucidation of mechanism of nystagmus underlying these two conditions. 
Footnotes
 Supported by the Ulverscroft Foundation.
Footnotes
 Disclosure: A. Kumar, None; I. Gottlob, None; R.J. Mclean, None; S. Thomas, None; M.G. Thomas, None; F.A. Proudlock, None
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Figure 1.
 
Original eye movement data in primary position (0°) and 15° to right (+15°) and left (−15°) for (A) an albino volunteer and (B) an FRMD7-IIN subject. (C) Right beating, left beating, and quiet phases are shown for an albinism volunteer with periodic alternating nystagmus.
Figure 1.
 
Original eye movement data in primary position (0°) and 15° to right (+15°) and left (−15°) for (A) an albino volunteer and (B) an FRMD7-IIN subject. (C) Right beating, left beating, and quiet phases are shown for an albinism volunteer with periodic alternating nystagmus.
Figure 2.
 
The proportion of waveform types from the classification given by Dell'Osso and Daroff 8 for the albino and the FRMD7 group. A greater proportion of pendular waveforms were observed in the FRMD7 group compared with albinism volunteers.
Figure 2.
 
The proportion of waveform types from the classification given by Dell'Osso and Daroff 8 for the albino and the FRMD7 group. A greater proportion of pendular waveforms were observed in the FRMD7 group compared with albinism volunteers.
Figure 3.
 
Means (error bars represent SEM) of (A) amplitude (log values), (B) frequency (log values), (C) intensity (log values), and (D) extended nystagmus acuity function (NAFX in logMAR) are shown during attempts to hold left (−15°) central (0°) and right gaze (+15°) for albinos and FRMD7-IIN volunteers.
Figure 3.
 
Means (error bars represent SEM) of (A) amplitude (log values), (B) frequency (log values), (C) intensity (log values), and (D) extended nystagmus acuity function (NAFX in logMAR) are shown during attempts to hold left (−15°) central (0°) and right gaze (+15°) for albinos and FRMD7-IIN volunteers.
Figure 4.
 
The probability that given a certain frequency of nystagmus for an individual taken at random from the whole data set that the nystagmus will be associated with albinism or FRMD7-IIN. The numbers shown next to the symbols indicate the percent of the whole group each point represents.
Figure 4.
 
The probability that given a certain frequency of nystagmus for an individual taken at random from the whole data set that the nystagmus will be associated with albinism or FRMD7-IIN. The numbers shown next to the symbols indicate the percent of the whole group each point represents.
Figure 5.
 
Visual acuity (converted to logMAR) in albinos and IIN associated with FRMD7 mutations (FRMD7-IIN).
Figure 5.
 
Visual acuity (converted to logMAR) in albinos and IIN associated with FRMD7 mutations (FRMD7-IIN).
Figure 6.
 
Comparisons of the percentage of (A) strabismus, (B) stereopsis, and (C) degree of anomalous head posture between albinos and IIN associated with FRMD7 mutations (FRMD7).
Figure 6.
 
Comparisons of the percentage of (A) strabismus, (B) stereopsis, and (C) degree of anomalous head posture between albinos and IIN associated with FRMD7 mutations (FRMD7).
Table 1.
 
Comparison of Clinical Findings to Previous Studies
Table 1.
 
Comparison of Clinical Findings to Previous Studies
Study Albinism IIN
logMAR Visual Acuity Strabismus (%) Stereopsis (%) AHP (%) logMAR Visual Acuity Strabismus (%) Stereopsis (%) AHP (%)
Abadi and Dickinson 10 0.4 to 1.0 90.5 4.0 −0.1 to 1.0
Brodsky and Fray 27 53.3 16.7
Gradstein et al. 28 * 0.0 to 1.2 74.1 40.0 63.0
Kerrison et al. 29 0.2 to 0.7 35.7
Self et al. 30 0.1 to 0.5 44.0
Present study† ‡ 0.2 to 1.0 71.2 19.2 51.1 −0.2 to 0.8 7.8 93.4 15.0
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