Shery Thomas

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

Structural Grading of Foveal Hypoplasia Using Spectral-Domain Optical Coherence Tomography: A Predictor of Visual Acuity?

PURPOSE To characterize and grade the spectrum of foveal hypoplasia based on different stages of arrested development of the fovea. Grading was performed using morphologic findings obtained by ultra high-resolution spectral-domain optical coherence tomography. Best-corrected visual acuity (BCVA) was calculated for different grades. DESIGN Observational case series. PARTICIPANTS AND CONTROLS Sixty-nine patients with foveal hypoplasia (albinism, n = 34; PAX6 mutations, n = 10; isolated cases, n = 14; achromatopsia, n = 11) and 65 control subjects were examined. METHODS A 7×7-mm retinal area was sampled using a 3-dimensional scanning protocol (743×75, A scans×B scans) with ultra high-resolution spectral-domain optical coherence tomography (SOCT Copernicus HR; 3-μm axial resolution). Gross morphologic abnormalities were documented. B-scans at the fovea were segmented using a longitudinal reflectivity profile. Logarithm of the minimum angle of resolution BCVA was obtained. MAIN OUTCOME MEASURES Grading was based on presence or absence of foveal pit and widening of the outer nuclear layer (ONL) and outer segment (OS) at the fovea. Quantitative measurements were obtained for comparing atypical foveal hypoplasia in achromatopsia. Best-corrected visual acuity was compared with the grade of foveal hypoplasia. RESULTS Four grades of foveal hypoplasia were distinguished: grade 1, shallow foveal pit, presence of ONL widening, presence of OS lengthening; grade 2, grade 1 but absence of foveal pit; grade 3, grade 2 but absence of OS lengthening; grade 4, grade 3 but absence of ONL widening. There was significant difference in visual acuity (VA) associated with each grade (P<0.0001). Grade 1 was associated with the best VA (median VA, 0.2), whereas grades 2, 3, and 4 were associated with progressively poorer VA with a median VA of 0.44, 0.60, and 0.78, respectively. The atypical features seen with foveal hypoplasia associated with achromatopsia were characterized by decreased retinal and ONL thickness and deeper foveal depth. CONCLUSIONS A structural grading system for foveal hypoplasia was developed based on the stage at which foveal development was arrested, which helps to provide a prognostic indicator for VA and is applicable in a range of disorders associated with foveal hypoplasia. Atypical foveal hypoplasia in achromatopsia shows different characteristics. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Congenital nystagmus: Randomized, controlled, double-masked trial of memantine/gabapentin

Nystagmus consists of involuntary to and fro movements of the eyes. Although studies have shown that memantine and gabapentin can reduce acquired nystagmus, no drug treatment has been systematically investigated in congenital nystagmus.

The Prevalence of Nystagmus: The Leicestershire Nystagmus Survey

PURPOSE Nystagmus, which can be infantile (congenital) or acquired, affects all ages. The prevalence of nystagmus in the general population is unknown. New genetic research and therapeutic modalities are emerging. Previous estimates have been based on wider ophthalmic epidemiologic studies within specific occupational or age groups. The authors carried out the first epidemiologic study to specifically establish the prevalence of nystagmus in Leicestershire and Rutland in the United Kingdom. METHODS Three independent data sources identified persons with nystagmus from the hospital and community. The first was a hospital-based questionnaire and clinical survey (n = 238). The visually impaired services (n = 414) and education services (n = 193) in Leicestershire provided the second and third separately obtained community-based sources of information. Capture-recapture statistical analysis was used to estimate prevalence. RESULTS The prevalence of nystagmus in the general population was estimated to be 24.0 per 10,000 population (95% confidence interval [CI], +/-5.3). The most common forms of nystagmus were neurologic nystagmus (6.8 per 10,000 population; 95% CI, +/-4.6), nystagmus associated with low vision such as congenital cataracts (4.2 per 10,000; 95% CI, +/-1.2), and nystagmus associated with retinal diseases such as achromatopsia (3.4 per 10,000 population; 95% CI, +/-2.1). Within ethnic groups, nystagmus was significantly more common in the white European population than in the Asian (Indian, Pakistani, other Asian backgrounds) population (P = 0.004). CONCLUSIONS The findings suggest that nystagmus is more common in the general population than previously thought. This may be of significance in resource allocation and health care planning.

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7

Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P < 0.0001). The amplitude of nystagmus was more strongly dependent on the direction of gaze in the FRMD7 group being lower at primary position (P < 0.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VAs in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.

Clinical and oculomotor characteristics of albinism compared to FRMD7 associated infantile nystagmus.

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 = 4.3 Hz, 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.

The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.

Stiff person syndrome with eye movement abnormality, myasthenia gravis, and thymoma

Stiff person syndrome (SPS) is a rare disorder of the central nervous system characterised by progressive fluctuating rigidity and painful spasms of the body musculature. We describe a patient with SPS with positive glutamic acid decarboxylase (GAD) antibodies who developed diplopia. Thymoma was detected by computed tomography (CT), and after thymectomy his symptoms improved. One month after thymectomy, he tested positive for antiacetylcholine receptor (AchR) antibodies. A 45 year old man presented with a four week history of back pain and stiffness of his trunk causing difficulty in bending forward and turning over while lying down, which he attributed to a minor injury sustained while playing squash. He later developed asymmetrical stiffness of the legs and difficulty walking. His past medical history was notable for an episode of dysphagia (two weeks’ duration) associated with heartburn six months ago; a gastroenterological evaluation and an endoscopy at that time were normal. He recovered spontaneously and there was no recurrence. On examination his mental status, speech, and cranial nerves were normal. He had exaggerated lumbar lordosis. Neurological examination showed normal bulk with increased tone of the flexors and extensors of the knee and ankles. Power and coordination were normal, deep tendon reflexes were brisk, but he had flexor plantar responses. There was no evidence of fatigable …

Treatment of acquired periodic alternating nystagmus with memantine: a case report.

We report a case of acquired periodic alternating nystagmus associated with common variable immunodeficiency and cutaneous sarcoid. The patient was initially treated with baclofen with minimal subjective improvement. We found a significant improvement in the patients symptoms and nystagmus intensity after treatment with memantine.