RESUMEN
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.
Asunto(s)
Proteínas del Citoesqueleto/genética , Genes Ligados a X , Proteínas de la Membrana/genética , Nistagmo Congénito/genética , Encéfalo/embriología , Encéfalo/metabolismo , Mapeo Cromosómico , Cromosomas Humanos X , Proteínas del Citoesqueleto/fisiología , Movimientos Oculares/genética , Movimientos Oculares/fisiología , Femenino , Regulación del Desarrollo de la Expresión Génica , Ligamiento Genético , Humanos , Masculino , Proteínas de la Membrana/fisiología , Mutación/fisiología , Linaje , Retina/metabolismoRESUMEN
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.
Asunto(s)
Proteínas del Citoesqueleto/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas de la Membrana/genética , Mutación/genética , Nistagmo Patológico/genética , Encéfalo/embriología , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Cohortes , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Feto , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Nistagmo Optoquinético/genética , Nistagmo Optoquinético/fisiología , Nistagmo Patológico/patología , Músculos Oculomotores/fisiopatología , Fenotipo , Reflejo Vestibuloocular/genética , Canales Semicirculares/patología , Canales Semicirculares/fisiopatologíaRESUMEN
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 VA's 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.
Asunto(s)
Proteínas del Citoesqueleto/genética , Enfermedades Hereditarias del Ojo/genética , Proteínas de la Membrana/genética , Mutación , Nistagmo Patológico/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Cromosomas Humanos X/genética , Percepción de Color , Percepción de Profundidad , Enfermedades Hereditarias del Ojo/fisiopatología , Enfermedades Hereditarias del Ojo/psicología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Enfermedades Genéticas Ligadas al Cromosoma X/psicología , Cabeza/patología , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Nistagmo Congénito/genética , Nistagmo Congénito/fisiopatología , Nistagmo Congénito/psicología , Nistagmo Patológico/fisiopatología , Nistagmo Patológico/psicología , Linaje , Postura , Estrabismo/genética , Agudeza VisualRESUMEN
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.