Congenital Nystagmus Patients Research Articles

Differences of ocular oscillations and neuro-retinal structures in patients with nystagmus caused by GPR143 and FRMD7 gene variants.

Mutations of G protein-coupled receptor 143 (GPR143) and FERM domain containing 7 (FRMD7) may result in congenital nystagmus (CN) in the first 6 months of life. We aimed to compare the differences in ocular oscillations between patients with these two gene mutations as well as the functional and structural changes in their retinas and visual pathways. Medical records were retrospectively reviewed to identify patients of congenital nystagmus with confirmed mutations in either GPR143 or FMRD7 genes from January 2018 to May 2023. The parameters of the ocular oscillations were recorded using Eyelink 1000 Plus. The retinal structure and function were evaluated using optical coherence tomography and multi-focal electroretinography (mERG). The visual pathway and optical nerve projection were evaluated using visual evoked potentials. The next-generation sequencing technique was used to identify the pathogenic variations in the disease-causing genes for CN. Twenty nystagmus patients of GPR143 and 21 patients of FMRD7 who had been confirmed by molecular testing between January 2018 and May 2023 were included. Foveal hypoplasia was detected only in patients with the GPR143 pathogenic variant. mERG examination showed a flat response topography in the GPR143 group compared to the FRMD7 group. VEP showed that bilateral amplitude inconsistency was detected only in the patients with GPR143 gene mutation. The amplitude and frequency of the ocular oscillations were not found to differ between patients with two different genetic mutations. Although the etiology and molecular mechanisms are completely different between CN patients, they may have similar ocular oscillations. A careful clinical examination and electrophysiological test will be helpful in making a differential diagnosis. Our novel identified variants will further expand the spectrum of the GPR143 and FRMD7 variants.

Electroretinography in congenital nystagmus patients with a normal fundus examination.

To identify the ophthalmic causes of congenital nystagmus with normal eye examination by electroretinography (ERG). Retrospective observational study. We reviewed the medical records of patients younger than 6months of age who presented between June 2008 and November 2011 with nystagmus and no other neurological signs following an otherwise normal eye examination. A complete ophthalmic examination and ERG (Nicolet Bravo system; Nicolet Biomedial & RETIscan; Roland Instruments), fundus photography, and Ishihara color test were performed to identify any ophthalmic causes of congenital nystagmus. Thirty-three patients met the criteria. Rod dysfunction was diagnosed in 4 patients (12.1%), cone dysfunction in 2 patients (6.1%), and cone-rod dysfunction in 1 patient (3.0%). The results of ERG were negative in 2 patients (6.1%). Idiopathic infantile nystagmus was diagnosed in the remaining 24 patients (72.7%) based on their normal ERG examination. In Korean congenital nystagmus patients with a normal fundus examination, achromatopsia and Leber's congenital amaurosis are uncommon causes. ERG is needed to make a definite diagnosis and provide prognostic information in congenital idiopathic nystagmus patients with a normal fundus examination.

Disrupted voxel-mirrored homotopic connectivity in congenital nystagmus using resting-state fMRI.

Idiopathic congenital nystagmus (CN) is a rare eye disease that can cause early blindness (EB). CN deficits are observed most frequently with oculomotor dysfunction; however, it is still unclear what neuromechanics underly CN with EB. Based on that visual experience requires the functional integration of both hemispheres, we hypothesized that CN adolescents with EB might exhibit impaired interhemispheric synchrony. Our study aimed to investigate the interhemispheric functional connectivity alterations using voxel-mirrored homotopic connectivity (VMHC) and their relationships with clinical features in CN patients. This study included 21 patients with CN and EB, and 21 sighted controls (SC), who were matched for sex, age and educational level. The 3.0 T MRI scan and ocular examination were performed. The VMHC differences were examined between the two groups, and the relationships between mean VMHC values in altered brain regions and clinical variables in the CN group were evaluated by Pearson correlation analysis. Compared with the SC group, the CN had increased VMHC values in the bilateral cerebellum posterior and anterior lobes/cerebellar tonsil/declive/pyramis/culmen/pons, middle frontal gyri (BA 10) and frontal eye field/superior frontal gyri (BA 6 and BA 8). No particular areas of the brain had lower VMHC values. Furthermore, no correlation with the duration of disease or blindness could be demonstrated in CN. Our results suggest the existence of interhemispheric connectivity changes and provide further evidence for the neurological basis of CN with EB.

Hierarchical clustering analysis of congenital nystagmus waveforms

Objective: To explore the feasibility of applying machine-learning hierarchical clustering algorithm to waveform-type automatic classification and diagnosis in congenital nystagmus (CN). Methods: A retrospective case series study. A total of 90 patients (90 eyes) diagnosed with CN at Tianjin Eye Hospital from December 2018 to September 2019 were included in the study, including 67 males and 23 females, aged (12±9) years old. Eye movement waveforms were recorded with the video eye tracker in all patients. Analyses with unsupervised machine-learning hierarchical clustering algorithm were performed on the normalized eye movement waveforms. The visualized clustering results were obtained for further waveform naming. The occurrence rate of each waveform type was calculated, and the correlation between the proportion of each waveform type and the visual function of CN patients was analyzed. Independent sample t-test and Pearson correlation analysis were used for statistical analysis. Results: The 46 620 cycles of validated waveforms from the 90 CN patients were categorized into 7 types of waveforms through machine-learning hierarchical clustering algorithm, named type Ⅰ, type Ⅱ, type Ⅲ, and types Ⅳ1-4, respectively. In the 46 620 cycles of eye movement waveforms from the 90 patients with CN, there were 14 259 cycles of type Ⅰ (30.59%), 11 498 cycles of type Ⅱ (24.66%), 4 083 cycles of type Ⅲ (8.76%), 5 430 cycles of type Ⅳ1 (11.65%), 3 451 cycles of type Ⅳ2 (7.40%), 3 015 cycles of type Ⅳ3 (6.47%), 2 663 cycles of type Ⅳ4 (5.71%) and 2 221 cycles of unclassified waveforms (4.76%). The waveforms of types Ⅰ, Ⅱ and Ⅲ corresponded to the 3 basic CN eye movement waveforms (velocity-increasing jerk waveform, velocity-decreasing jerk waveform and pendular waveform) described in the textbooks, and the waveforms of types Ⅳ1-4 were complex waveforms. The proportions of patients with the 7 types of waveforms were 78.89% (71 cases), 41.11% (37 cases), 17.78% (16 cases), 20.00% (18 cases), 7.78% (7 cases), 15.56% (14 cases) and 11.11% (10 cases), respectively. According to the results of automatic classification, 38 (42.22%) CN patients presented with only one type of waveforms, and the remaining 52 (57.78%) CN patients presented with two or more types of waveforms, including 23 (25.56%) patients with 3 or more types of waveforms and 5 (5.56%) patients with 4 types of waveforms. The proportions of type Ⅰ component were significantly correlated with the patients' best corrected visual acuities (BCVAs;logarithm of the minimum angle of resolution) (r=-0.39; P<0.01), and there was no relationship between the proportions of type Ⅱ component and the patients' BCVAs (P>0.05). The BCVAs of the patients with type Ⅰ as the dominant component were better than those of the patients with type Ⅱ as the dominant component, with statistically significant difference (0.19±0.14 vs. 0.45±0.37;t=2.77; P<0.05). Conclusion: Machine-learning hierarchical clustering algorithm can be used for waveform-type automatic classification and discrimination in CN and provide an auxiliary method for the precise diagnosis and evaluation of the disease.

A new measure of nystagmus acuity.

To construct a new visual acuity measuring function for congenital nystagmus (CN) patients by studying the relationships between acuity, velocities and positions of the eye. After assessing the relationship between acuity, movement velocities and positions of the eye separately, a new function, which we call the automated nystagmus acuity function (ANAF), was constructed to measure the visual acuity of CN patients. Using a high-speed digital video system working at 500 frames per second, each eye was calibrated during monocular fixation. Twenty-six recorded nystagmus data were selected randomly. Using nystagmus waveforms, the best vision position (foveation period) and visual acuity were analyzed in three groups of subjects, and then all outputs were compared with the well-known expanded nystagmus acuity function (NAFX) and ANAF. Standard descriptive statistics were used to summarize the outputs of the two programs. Foveation periods were brief intervals in the CN waveform when the image was on or near the fovea and eye velocity was relatively slow. Results showed good visual acuity happened during the period when velocity was low and the eye position was near the zero position, which fitted the foveation periods. The data analyzed with NAFX and ANAF had a correlation coefficient of 0.934276, with an average error of -0.00973. The results from ANAF and NAFX analyses showed no significant difference. The NAFX manually identifies foveation eye positions and produces accurate measurements. The ANAF, however, can be calculated simply using the factors eye position and velocity, and it automatically calculates the ANAF without the need to manually identify foveation eye positions.

A novel splicing site mutation of the GPR143 gene in a Chinese X-linked ocular albinism pedigree

Ocular albinism is an X-linked inherited disease characterized by hypopigmentation of the iris and nystagmus. To identify a new disease-causing mutation of ocular albinism, we collected a Han Chinese pedigree with 7 male congenital nystagmus patients over 3 generations. Slit-lamp photography and optical coherence tomography were performed for the proband. Genomic DNA was extracted from a whole blood sample from the proband using the high-salt method. Polymerase chain reaction (PCR) sequencing was carried out for GPR143 and FRMD7 genes. The three-dimensional structures of the wild-type and mutant GPR143 proteins were determined using SWISS-MODEL. The transmission of the disease in the pedigree clearly followed an X-linked pattern. The proband had significant iris and fundus hypopigmentation. Optical coherence tomography showed severe foveal hypoplasias in both eyes of the proband. A novel splicing site (G/C) mutation was found on the boundary of the 6th intron and the 7th exon of the GPR143 gene, resulting in a 9-amino-acid deletion (codons 257-265) in the 6th transmembrane domain of the GPR143 protein. In conclusion, a novel splicing site mutation of the GPR143 gene was found in a Han Chinese congenital ocular albinism pedigree.

Spectral-domain optical coherence tomography in patients with congenital nystagmus.

To study macular features in patients with congenital nystagmus and to assess the utility of spectral-domain optical coherence tomography (SD-OCT) in nystagmus. The macular areas of 51 outpatients with congenital nystagmus were examined using SD-OCT. Morphological changes in the retinal layers of the macular area were analysed. Macular images were successfully obtained with SD-OCT from 50 (98%) patients. Patients with ocular albinism mainly have macular hypoplasia, abnormal foveal depression, and increased foveal thickness with persistence of an inner nuclear layer, an inner plexiform layer, a ganglion cell layer and a nerve fiber layer. Macular morphology similar to albinism was observed in three patients with idiopathic macular hypoplasia. The OCT findings of cone dystrophy included unclear, disrupted or invisible photoreceptor outer segment/inner segment in the fovea; fusion, thickening and uneven reflection of the outer segment/inner segment with external limiting membrane. Some patients with congenital idiopathic nystagmus showed normal macular morphology and structure, and others showed indistinct macular external limiting membrane reflection. SD-OCT is an effective and reliable method to detect the macular morphology of congenital nystagmus patients. This technique has diagnostic value in particular for patients with macular hypoplasia and cone cell dystrophy with no distinct abnormality on fundoscopy.

Characterisation of baseline oscillation in congenital nystagmus eye movement recordings

Congenital nystagmus is an ocular–motor disorder that develops in the first few months of life; its pathogenesis is still unknown. Patients affected by congenital nystagmus show continuous, involuntary, rhythmical oscillations of the eyes. Monitoring eye movements, nystagmus main features such as shape, amplitude and frequency, can be extracted and analysed. Previous studies highlighted, in some cases, a much slower and smaller oscillation, which appears added up to the ordinary nystagmus waveform. This sort of baseline oscillation, or slow nystagmus, hinder precise cycle-to-cycle image placement onto the fovea. Such variability of the position may reduce patient visual acuity. This study aims to analyse more extensively eye movements recording including the baseline oscillation and investigate possible relationships between these slow oscillations and nystagmus. Almost 100 eye movement recordings (either infrared-oculographic or electrooculographic), relative to different gaze positions, belonging to 32 congenital nystagmus patients were analysed. The baseline oscillation was assumed sinusoidal; its amplitude and frequency were computed and compared with those of the nystagmus by means of a linear regression analysis. The results showed that baseline oscillations were characterised by an average frequency of 0.36 Hz (SD 0.11 Hz) and an average amplitude of 2.1° (SD 1.6°). It also resulted in a considerable correlation ( R 2 scored 0.78) between nystagmus amplitude and baseline oscillation amplitude; the latter, on average, resulted to be about one-half of the correspondent nystagmus amplitude.

Baclofen for Patients with Congenital Periodic Alternating Nystagmus

Introduction: Nystagmus degrades visual acuity by reducing the stability of fixation and lessening foveation time. PAN (periodic alternating nystagmus) is underrecognized in congenital nystagmus patients and may be a component of the nystagmus in up to 9% of these patients. It may also develop with time. Method: A retrospective review of patients was carried out between 1999 and 2004 with congenital idiopathic nystagmus with a PAN waveform treated with Baclofen. Seven patients were identified, five males and two females, with an average age at treatment of 19 years (range 9 to 32 years).

Pathophysiology and diagnosis of congenital periodic alternating nystagmus

Purpose Not many cases of congenital periodic alternating nystagmus have been reported in Japan. We investigated the pathophysiology and diagnosis of congenital periodic alternating nystagmus, noting the age when this disease began, which had not been reported previously. Subjects Ninety-one patients with congenital nystagmus who were seen in our department in the Teikyo University School of Medicine between July 1994 and January 2002 were studied. Results Eighteen patients (19.8%) among the 91 congenital nystagmus patients were diagnosed with congenital periodic alternating nystagmus. A manifestation of the periodic face turning was seen between the ages of 3 and 9 years. Visual acuity over 0.6 with correction was obtained in all patients. Almost all the patients had an asymmetric cycle of null point shifting, and the face turning was seen at one side for a long time. Conclusion When we see congenital nystagmus patients whose face turning alters periodically with fairly good vision over the age of three, we must check out the direction of jerk nystagmus changes at the same gazing point using electronystagmography or video cassette recording to detect the possibility of congenital periodic alternating nystagmus.

Best catch from NANOSNET.

Best catch from NANOSNET.

The role of vision on postural strategy evaluated in patients affected by congenital nystagmus as an experimental model

The role of vision in postural control is crucial and is strictly related to the characteristics of the visual stimulus and to the performance of the visual system. The purpose of this investigation was to evaluate the effects of chronically reduced visual cues upon postural control in patients affected by Congenital Nystagmus (CN). These patients have developed since birth a postural strategy mainly based on vestibular and somatosensorial cues. Fifteen patients affected by CN and 15 normal controls (NC) were enrolled in the study and evaluated by means of dynamic posturography. The overall postural control in CN patients was impaired as demonstrated by the equilibrium score and by the changes of the postural strategy. This impairment was even more enhanced in CN than in NC group when somatosensorial cues were experimentally reduced. An aspecific pattern of visual impairment and a pathological composite score were also present. Our data outline that in patients affected by CN an impairment of the postural balance is present especially when the postural control relies mainly on visual cues. Moreover, a decrease in accuracy of the somatosensory cues has a proportionally greater effect on balance than it has on normal subjects.

Vestibular perception of angular velocity in normal subjects and in patients with congenital nystagmus.

A technique is described for the assessment of vestibular sensation. The two main goals of the study were (i) to compare the perception of angular velocity with the eye velocity output of the vestibulo-ocular reflex and (ii) to study vestibular function in patients with congenital nystagmus; this was needed since most previous studies, based on eye movement recordings, have been inconclusive. Subjects indicated their perceived angular velocity by turning by hand a wheel connected to a tachometer. The vestibular stimuli used consisted of sudden deceleration from rotation at a constant horizontal velocity of 90 degrees /s ('stopping' responses). Eye movements were recorded simultaneously with electro-oculography. In normal subjects the perceived angular velocity decayed from the moment of deceleration in an exponential fashion. The mean time constant of sensation decay was approximately 16 s. Eye movement velocity decayed with a similar exponential trajectory (time constant 16 s). Congenital nystagmus patients showed markedly shortened vestibular sensation (mean time constant 7 s). The following conclusions can be drawn: (i) the similarity of the eye velocity and perceptual responses suggests that these two systems receive a vestibular signal which has been similarly processed; (ii) the time constant of the responses indicates that this vestibular signal probably originates in the same brainstem 'velocity storage' integrator; (iii) the technique described is useful for clinical assessment of vestibular function, particularly in patients with ocular motility disorders; (iv) patients with congenital nystagmus have short vestibular time constants, which is probably due to changes induced in velocity storage processing by the persistent retinal image motion present in these patients.

Congenital nystagmus: In search of simplicity on the other side of complexity

To the Editor: This letter is in response to a recent editorial, “Congenital Nystagmus: In Search of Simplicity on the Other Side of Complexity,“1 written about the paper, “Clinical and Ocular Motor Analysis of Congenital Nystagmus in Infancy.“2 The paper in question (1) is the first prospective study of the waveforms of congenital nystagmus (CN) in infants; (2) contains the largest population so studied; (3) is the first such study to use accurate and sensitive ocular motor recording techniques; and (4) provides the first demonstration that infants do exhibit the same CN waveforms as adults, with breaking saccades, foveating saccades, and foveation periods (ie, they are not all pendular, as others have suggested). We recognize the connection in those CN patients with sensory disorders and also provide an explanation of the mechanism by which afferent disorders can facilitate the disorder of the smooth pursuit system to properly calibrate and thereby result in CN. This was done in the text and in Figure 11. Also, despite the adequate functioning of the smooth pursuit in CN subjects (ie, the velocity gain is normal), the readers of our paper can arrive at the conclusion that CN may be directly caused by the normally damped oscillations of the smooth pursuit system. We are well aware of, and largely responsible for, the overwhelming evidence that smooth pursuit is “intact” in CN (see references 19 and 20 in our paper). We were also careful to differentiate between those conditions that mightfacilitate the development of CN and what current evidence suggests is the direct cause. We would not presume to coerce any clinicians into altering their decisions to continue to use the terms sensory CN and motor CN. We welcome Dr Hamed’s wish to “bridge the gap between basic scientists and pediatric ophthalmologists” (although that was not an issue for us-one of the authors of our paper is a pediatric ophthalmologist). For the record, (1) CN is a single motor sign reflecting the primary oscillations of smooth pursuit and the secondary attempts by the saccadic and fixation subsystems to acquire the target of interest and prolong its capture by the fovea; (2) afferent deficits are neither necessary nor sufficient for the development of CN; (3) CN can only be reliably and repeatedly diagnosed and differentiated from other forms of nystagmus with the aid of ocular motor recordings; and (4) the diagnosis of CN should always prompt the ophthalmologist to assess the afferent visual system, despite the absence of direct causality. We will continue to investigate in the hope of clarifying and to report in the hope of converting the existing confusion on this side to the simplicity of understanding on the other.

Ultrastructural Study of Extraocular Muscle in Congenital Nystagmus

To determine the mechanism of congenital nystagmus (CN), the ultrastructure of the extraocular muscle in CN patients was examined with the transmission electron microscope. The specimen of muscle tissue was taken during surgery from horizontal recti in the slow and quick phase sides separately in the jerky type, and medial and lateral recti in the pendular type. The extraocular muscle was immediately fixed in 2.5% glutaraldehyde solution. (1) In the jerky type, the myocytes in the quick phase side showed myofibrillae that were perpendicular to axes of myocytes and had the structure of sarcomeres. In the slow phase side there were perpendicular myofibrillae in the periphery of myocytes. (2) In the pendular type, there were no perpendicular myofibrillae within myocytes. The myofibrillae that were parallel to the axes of myocytes were arranged disorderly. The length of the H and I bands in different myofibrillae was not identical. These results demonstrated, for the first time, the ultrastructural changes in the extraocular muscle of CN patients, which might provide the pathological basis for this disease.

Visually induced motion perception and visual control of postural sway in congenital nystagmus

In congenital nystagmus (CN) the threshold for detecting motion of visual objects is increased. To determine whether this increase is due to a deterioration of visual motion signals or whether visual-vestibular interactions (which are necessary to judge object-motion in space) are also involved we examined how CN patients use visual motion signals to evaluate self-motion in perceptual and behavioral tasks. Using an optokinetic drum we measured the minimum optokinetic acceleration necessary to induced motion perception of the visual environment in CN patients. This threshold was significantly elevated in the CN patients compared with normals (20.1 deg/s 2 to 3.25 deg/s 2). We further addressed the question whether the elevation of this threshold is due to a deficiency in evaluating visual motion in general or to a specific modification affecting the percept of visual object-motion with respect to the inertial reference only. We thus measured the latency of visually induced self-motion perception, which was found to be very similar or even slightly smaller (1.7±0.7 s) compared with normals (2.2±1.7 s). Moreover, subjects with CN were found to use vision quite efficiently for the visual stabilization of posture (Romberg quotient 2.0±1.16), even if they did not reach the level of normals (Romberg quotient 3.7±1.1). The results indicate that CN affects the estimate of object-motion in a specific and much more severe way than the estimate of self-motion. The minimal effect of CN on self-motion perception can be explained by the low pass characteristics of the optokinetic input to self-motion perception. The specific deficiency in detecting object-motion indicates that adaptation to CN occurs on the level of visual–vestibular interactions for the perception of visual object-motion and not on the level of visual motion signals.

The effects of afferent stimulation on congenital nystagmus foveation periods

Visual acuity in congenital nystagmus (CN) patients is related primarily to the duration of “foveation periods”, during which the image of the target is relatively stationary in the foveal area. Thirteen individuals with CN were studied to test the hypothesis that somatosensory stimulation (vibration or electrical) of either the forehead or the neck damps CN and improves visual acuity. We identified characteristics of the nystagmus waveform that were likely to be important in determining visual acuity and combined these measures into an “acuity function” (NAFP) that correlated well with visual acuity ( r 2 = 0.91). Statistically significant changes in NAFP were used to assess the effects of afferent stimulation; positive effects were found in nine subjects. Vibratory stimulation (especially on the neck) was found to be more effective than electrical stimulation. CN amplitude reduction alone was neither necessary nor sufficient to improve acuity. Foveation duration was the single most important factor determining acuity. Based on our findings, afferent stimulation should be considered as an alternative or additional treatment to improve visual acuity in CN patients.

Fast-phase instabilities in normally sighted relatives of congenital nystagmus patients--autosomal dominant and x-chromosome recessive modes of inheritance.

Verification of inheritance in congenital nystagmus (CN) is only possible through the identification of more than one affected member in a family since in a single case there are no accurate clinical differentiations between "spontaneous" and inherited CN. We performed electronystagmographic examinations (ENG) to search for abnormal involuntary eye movements as a sign of heredity in seemingly unaffected members of CN families. ENG registrations were performed under three test conditions: (1) with the subject fixating a target, (2) with the room lights off and (3) with closed eyes. Fifty normally sighted individuals (group (a] underwent the test procedure to provide a baseline of normality. Five CN families (three dominant, two sex-linked recessive) were tested as group (b). The eye movement recordings were analysed in terms of nystagmus intensity (amplitude x frequency of the involuntary saccade). In every one of the five families, abnormalities in seemingly non-affected members could be demonstrated: in four families, fast-phase instabilities, in the fifth family a true (CN) (slow-phase instability). All certain gene carriers were diagnosed correctly by the ENG. These findings indicate a method for detecting slightly affected members in dominant pedigrees and female gene carriers in sex-linked mode of transmission.

Evaluation of smooth pursuit in the presence of congenital nystagmus

Studies of the ability of patients with congenital nystagmus (CN) to pursue a moving target have yielded conflicting conclusions. This paper reviews pursuit records dating from the first quantitative eye movement study of smooth pursuit and CN (with its hypothesis of superposition of normal pursuit onto the CN) to more recent records obtained when such patients pursue a moving target. Correct interpretation of the resulting ocular motility data is dependent upon the understanding of CN waveform and direction changes, null shifts and target foveation that has emerged in the 20 years since that first study. The data support the conclusion that the smooth pursuit system in CN patients is intact, using both retinal slip velocity and position information to match eye velocity and position to those of the target. An updated model of the author's original hypothesis is included to illustrate how this is possible. Thus, the mechanisms used are identical to those employed by normals and differences in the resultin...