DiagnosisClinical Diagnosis The diagnosis of FRMD7-related infantile nystagmus (FIN) should be considered in an individual with the following findings [Thomas et al 2008]: Note: Findings are those typically encountered during examination of an affected individual; the typical presentation may vary. Onset of nystagmus during infancy (age ≤6 months)Horizontal and conjugate nystagmus oscillationsAmplitude of nystagmus that is gaze dependent (i.e., small amplitude on central gaze when compared to left and right gaze)
Note:Eye movement recordings are helpful in evaluating:The nystagmus waveform characteristics including conjugacy, direction of oscillations (quick phase), pattern of oscillations (pendular, jerk, or bidirectional waveforms), and plane of oscillations (horizontal, vertical, and torsional); and Quantitative features of the waveform including frequency, amplitude, foveation dynamics, and null point width (range of eye eccentricities in which the nystagmus is quietest). Affected individuals typically exhibit a pendular or jerk-related waveform with horizontal and conjugate oscillations. In the jerk waveform, the slow phase has an increasing velocity.Amplitude and direction of the quick phase that may be time dependent (periodic alternating nystagmus) [Thomas et al 2011a]Visual acuity that is typically better than 0.3 LogMAR (Snellen equivalent 6/12)Good binocular vision and normal color visionFamily history of nystagmus consistent with X-linked inheritanceFindings that may occur in FIN include dampening of the nystagmus by convergence.Findings that occur less commonly in FIN include the following:Anomalous head posture (15% of affected individuals)Strabismus (8% of affected individuals) Normal findings often encountered in the course of the diagnostic evaluation of an individual with FIN include the following:Slit-lamp biomicroscopy (normal iris pigmentation with no iris transillumination) Fundoscopy (normal fundus) Cranial MRI (normal)Electrodiagnostic testsElectroretinogram (ERG) (normal)Visual evoked potentials (VEPs) (normal)Molecular Genetic Testing Gene. FRMD7 (FERM domain-containing 7) (locus name NYS1) is the only gene in which mutation is known to cause FRMD7-related infantile nystagmus.Clinical testing Sequence analysis. Once a clinical diagnosis of FRMD7-related infantile nystagmus is suspected (see Clinical Diagnosis) sequence analysis can be used to confirm mutations of FRMD7 [Tarpey et al 2006, Schorderet et al 2007, Self et al 2007, Zhang et al 2007a, Zhang et al 2007b, He et al 2008, Kaplan et al 2008, Pu et al 2011, Thomas et al 2011a]. Deletion/duplication analysis. Fingert et al [2010] reported the identification of an FRMD7 deletion involving exons 2, 3, and 4 in all affected males from a large three-generation family with X-linked infantile nystagmus. Table 1. Summary of Molecular Genetic Testing Used in FRMD7-Related Infantile NystagmusView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityFRMD7Sequence analysis of exons and splice sites Sequence variants 2, 383%-94% 3, 4Clinical Deletion / duplication analysis 5Deletion of one or more exons or the whole geneUnknown1. Percent of disease alleles detected in individuals with a phenotype characteristic of FIN and a positive family history. Note: Data apply to males and heterozygous females.2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. 4. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. Testing StrategyTo establish the diagnosis in a proband. The presence of infantile nystagmus and relatively good visual acuity (in most cases better than 6/12) in the absence of other ocular and neurologic diseases suggests a diagnosis of idiopathic infantile nystagmus (IIN). In addition to the above findings, a family history of X-linked inheritance strongly suggests the diagnosis of FIN. In some families with X-linked inheritance females can also exhibit nystagmus; thus, X-linked inheritance should still be considered even in families with females exhibiting nystagmus.Therefore, the primary aim of testing in such individuals is to rule out other causes of infantile nystagmus and establish the clinical characteristics of the condition. The examination should evaluate:Visual acuity Color visionStrabismusBinocularityOcular motilityHead postureThis should be supplemented by detailed ophthalmic examination and electrodiagnostic investigations including:Slit-lamp examinationFundus examinationMeasurement of refractive error VEPsERGNote: (1) In some centers more sophisticated investigations including ocular motility recordings can be performed. From the ocular motility recordings one can establish whether there are cyclical changes in the nystagmus amplitude and quick phase direction. An extended fixation task is required to diagnose periodic alternating nystagmus.Confirming the diagnosis in a proband. Molecular genetic testing of FRMD7 is performed to establish the diagnosis of FRMD7-related infantile nystagmus. Sequence analysis should be performed first. Deletion/duplication analysis may be appropriate to confirm a putative deletion detected by sequence analysis in a male.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in FRMD7.}

Natural History Affected individuals usually develop nystagmus within the first six months of life; the mean age of onset is two months. Nystagmus can be gaze-dependent oscillations or time-dependent oscillations (periodic alternating nystagmus). Nystagmus waveform characteristics are established by eye movement recordings that assess the following (see Figure 1 and Figure 2):FigureFigure 1. Eye rotation can occur about three axes (X, Y, Z). Torsional eye movements occur along the line of sight (X); horizontal and vertical eye movements occur along the Z and Y axes, respectively. The oscillations seen in FIN occur only in the horizontal (more...)FigureFigure 2. The horizontal eye movement recordings in an individual with FIN
(a) Gaze-dependent nystagmus. Note the right-beating pattern on right gaze.
(b) Components of a jerk waveform. Note the increasing velocity of the slow phase and (more...)ConjugacyPlane of oscillations (horizontal, vertical, and torsional) Pattern of oscillations (pendular, jerk, or bidirectional waveforms)Direction of oscillations (quick phase)Quantitative features of the waveform, including:FrequencyAmplitudeFoveation dynamics (Foveation is the period during which the eyes remain relatively still and the image is incident on the fovea.)Null point width (range of eye eccentricities in which the nystagmus is quietest) Note: The quantitative features of the waveform can only be evaluated using eye movement recordings. The above measurements also help in assessing the clinical severity of the nystagmus. Conventionally, intensity (product of amplitude and frequency) is measured in order to describe the severity of nystagmus; however, foveation correlates best with visual function scores. Foveation takes into account both the retinal image velocity and position of the image in relation to the fovea. An example of the measure of foveation is the NAFX (extended nystagmus acuity function), which assesses the standard deviation of the aforementioned parameters and the duration of the foveation. Measuring intensity, foveation characteristics, and null point width before and after treatment provides an objective measure of the therapeutic response. Numerous studies have shown that the predominant waveform changes with age (see Table 2). In a unique case report, eye movements were described and recorded before the onset of nystagmus [Gottlob 1997].At the onset, large-amplitude, low-frequency horizontal eye movements (described as triangular eye movements) are seen. This waveform pattern is followed by a smaller-amplitude pendular or jerk waveform and development of foveation. Another study reported that the predominant waveform during the first six months was asymmetric pendular and jerk with extended foveation [Hertle et al 2002]. Table 2. How the Infantile Nystagmus Waveform Evolves: An ExampleView in own windowAge Waveform Description5 weeks ^{1No nystagmus7 weeksSquare wave jerk8 weeksSmall pendular nystagmus10 weeksLarge jerk type nystagmus14 weeksSmall pendular nystagmus7-12 monthsConjugate pendular nystagmusGottlob [1997]1. The infant was initially part of another study looking at normal visual development. In adults, a pendular waveform is more commonly associated with FRMD7-related infantile nystagmus (FIN) than with non-FRMD7 ideopathic infantile nystagmus (IIN) (see Differential Diagnosis) [Thomas et al 2008]. These oscillations are accentuated by attention, anxiety, attempts to fixate on an object, and directing the gaze away from the null zone. Individuals with FIN report good visual acuity (typically better than 6/12) because the nystagmus waveform is interrupted by a foveation period and, in contrast to other forms of infantile nystagmus, FIN is not the result of sensory abnormalities (e.g., reduced visual acuity resulting from foveal hypoplasia) (see Differential Diagnosis). An abnormal head posture is seen in approximately 15% of affected individuals. Affected individuals may assume an anomalous head posture if they have an eccentric null zone. Titubation of the head is observed in some individuals. However, affected individuals do not report any tremor of the limbs or trunk or any balance or coordination problems. Oscillopsia, the illusion of movement in one’s surroundings, is very rarely reported in FIN. This may result in part from the presence of foveation periods during the waveform. However, an affected individual may complain of oscillopsia when looking at a position of gaze in which the nystagmus is more pronounced or when the individual is tired. Affected females report slightly better visual acuity than affected males. However, no notable differences in amplitude, frequency, and waveform of nystagmus are observed between males and females. Idiopathic infantile periodic alternating nystagmus is a subtype of IIN in which the direction of the quick phase alternates with time. It can be caused by mutations in FRMD7 in familial cases and simplex cases (i.e., a single occurrence in a family). The phenotype is almost identical to that observed with IIN except the nystagmus changes direction. It has been suggested that this could be the result of a shifting null zone. None of the individuals with periodic alternating nystagmus had an optokinetic response [Thomas et al 2011a].}

Genotype-Phenotype CorrelationsStudies have shown extensive intra- and interfamilial variability in the phenotype [Self et al 2007, Shiels et al 2007, Thomas et al 2008]. The familial idiopathic infantile periodic alternating nystagmus phenotype is predominantly associated with missense mutations [Thomas et al 2011a].

Differential DiagnosisThe diagnosis of FRMD7-related infantile nystagmus (FIN) can be challenging as numerous causes of infantile nystagmus can present with conjugate horizontal oscillations of the eyes and reduced visual acuity. Individuals with infantile nystagmus need to be diagnosed with idiopathic infantile nystagmus (IIN) prior to inferring a diagnosis of FIN. Therefore, individuals with infantile nystagmus typically undergo a myriad of tests primarily to rule out other causes of infantile nystagmus because IIN is considered a diagnosis of exclusion [Hertle et al 2002]. IIN with a family history of X-linked inheritance suggests FIN, whereas IIN in the absence of a family history suggests non-FRMD7 IIN. Using eye movement recordings one can determine whether there is a periodic component to the nystagmus which suggests the diagnosis of periodic alternating nystagmus. Non-FRMD7 IIN is characterized by infantile nystagmus and reduced visual acuity. It is not associated with any other sensory pathologies. Color vision, slit-lamp examination, ERG, and VEP are normal. Strabismus is uncommon (~10% of affected individuals). Eye movement recordings show conjugate horizontal oscillations with an increasing slow phase velocity. Non-FRMD7 IIN is similar to FIN; distinguishing signs include: Abnormal head posture and eccentric null zone; Amplitude of the nystagmus that is not as significantly dependent on gaze as in FIN; Pendular waveform that is not as commonly encountered as in FIN. The cause of non-FRMD7 IIN is unknown. Affected individuals rarely have a family history of nystagmus; in rare cases autosomal dominant inheritance has been reported [Klein et al 1998, Kerrison et al 1999, Hoffmann et al 2004]. Kerrison et al [1999] reported a large family with autosomal dominant inheritance of infantile nystagmus. The visual acuity ranged from 20/30 to 20/100 and 36% of family members had strabismus. Linkage analysis demonstrated that the gene responsible is likely to be located within an 18-centimorgan (cM) region between markers D6S271 and D6S455 on the short arm of chromosome 6. This is referred to as the NYS2 locus. Klein et al [1998] reported a smaller family (3 affected members in a 2-generation family) with suspected autosomal dominant inheritance of nystagmus. However there was no male-to-male transmission. Linkage analysis demonstrated that the phenotype could arise as a result of the common haplotype shared by the affected members at 7p11.2 (NYS3). Ragge et al [2003] described an additional locus (NYS4; 13q31-q33) responsible for autosomal dominant nystagmus. However the phenotype was quite distinct from the previously reported forms of idiopathic infantile nystagmus because of the vestibulocerebellar signs which included upbeat nystagmus. There is some evidence for an additional locus (NYS5) for idiopathic infantile nystagmus on the X-chromosome. Cabot et al [1999] reported a four-generation French family with X-linked idiopathic infantile nystagmus. Linkage analysis demonstrated mapping to Xp11.4-11.3 between the polymorphic markers DXS8015 and DXS1003. Albinism. All forms of albinism are characterized by infantile nystagmus. Individuals with albinism have ocular findings not present in FIN that include: hypopigmentation of the iris pigment epithelium evident as iris transillumination on slit-lamp examination; hypopigmentation of the ocular fundus; foveal hypoplasia; and misrouting of axons in the optic chiasm evident on VEP as crossed asymmetry of the cortical responses and abnormalities in the primary visual cortex. Visual acuity is much poorer in all forms of albinism (mean VA = 0.67 LogMAR; Snellen equivalent = 6/28) [Abadi & Bjerre 2002] than in FIN. In albinism binocular vision is poor and strabismus is common.The most common forms of albinism are the following:Oculocutaneous albinism (OCA). Characteristic eye findings plus reduced pigmentation of the skin and hair are present. The four types of OCA are OCA1 (caused by mutations in TYR), OCA2 (caused by mutations in OCA2), OCA3 (caused by mutations in TYRP1), and OCA4 (caused by mutations in SLC45A2). Inheritance is autosomal recessive in these four types.X-linked ocular albinism is caused by mutations in GPR143. Similarities to FIN include normal hair and skin pigmentation and X-linked inheritance. Chediak-Higashi syndrome (CHS) is characterized by partial OCA, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system. Adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogeneic hematopoietic stem cell transplantation develop neurologic findings during early adulthood that include low cognitive abilities, balance abnormalities and ataxia, tremor, absent deep-tendon reflexes, and motor and sensory neuropathies. LYST, previously known as CHS1, is the only gene in which mutation is known to cause CHS. Inheritance is autosomal recessive.Achromatopsia, a disorder of cone function, is characterized by reduced visual acuity, pendular or jerk nystagmus, photophobia, a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. In achromatopsia color discrimination is impaired along all three axes of color vision corresponding to the three cone classes: the protan, or long-wavelength-sensitive cone axis (red); the deutan, or middle-wavelength-sensitive cone axis (green); and the tritan, or short-wavelength-sensitive cone axis (blue). In achromatopsia the ERG photopic response is absent or markedly diminished, whereas the scotopic response is normal or mildly abnormal. Optical coherence tomography studies also show a characteristic lesion at the fovea with outer nuclear layer thinning [Thiadens et al 2010, Thomas et al 2011b]. The normal color vision observed in FIN can distinguish between the two conditions. When color vision is difficult to test in young children, ERG can be used. Mutations of CNGB3, CNGA3, GNAT2, and PDE6C are causative. Inheritance is autosomal recessive.Blue cone monochromatism, resulting from the absence of both green and red cone sensitivities, is characterized by reduced visual acuity (although better than in achromatopsia), infantile nystagmus, and photophobia. The photopic ERG is reduced, but the S cone ERG is well preserved. Mutations in the red and green visual pigment gene cluster are causative. Inheritance is X-linked. See Red-Green Color Vision Defects, Genetically Related Disorders.X-linked congenital stationary night blindness (CSNB) is characterized by non-progressive retinal findings of reduced visual acuity, defective dark adaptation, refractive error, infantile nystagmus, strabismus, normal color vision, and normal fundus examination. The two types of X-linked CSNB are: CSNB1, caused by NYX mutations, and CSNB2, caused by CACNA1F mutations. Individuals with complete X-linked CSNB (CSNB1) generally report severe night blindness whereas individuals with incomplete X-linked CSNB (CSNB2) do not uniformly report severe night blindness. Scotopic ERG shows severely reduced (or absent) b-waves in CSNB1 and reduced but measurable b-waves in CSNB2. The absent b-wave is sometimes referred to a “negative ERG.” FIN can be differentiated from CSNB based on ERG studies. Inheritance is X-linked.Leber congenital amaurosis (LCA) is a severe dystrophy of the retina that typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, and refractive errors. Visual acuity is rarely better than 6/120. An associated finding in LCA is the oculodigital sign. Individuals with LCA have an extinguished or severely reduced scotopic and photopic ERG. FIN can be distinguished based on visual acuity measurements and ERG findings. However, because measuring visual acuity in infants can be difficult, ERG is the test of choice for distinguishing between the two disorders in infants. Mutations in eight genes have been reported to cause LCA. Inheritance is autosomal recessive in most families, although autosomal dominant inheritance has been reported.Other. Nystagmus in childhood can also be associated with other disorders such as aniridia, retinopathy of prematurity, dystrophies of retinal photoreceptors (including Joubert syndrome and Bardet-Biedl syndrome), congenital cataract, optic disc atrophy, and optic nerve hypoplasia. Other syndromes that can present with nystagmus during infancy include Down syndrome and spasmus nutans [Gottlob 2000]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with FRMD7-related infantile nystagmus (FIN), the following are recommended:Evaluation of visual acuity at different gaze positions [Yang et al 2005]Recording eye movements to evaluate the nystagmus waveform: Amplitude, frequency, and conjugacyFoveation dynamicsNull point width determinationIn individuals with periodic alternating nystagmus, recording of cycle duration and the presence of an alternating head posture Treatment of ManifestationsOptical devicesCorrection of refractive errors as early as possible using contact lenses or appropriate refractive correction can improve visual acuity appreciably. Contact lenses not only provide optical correction but also may have a role in dampening the intensity of the nystagmus. Although the mechanism is not clear, it has been suggested that dampening of the nystagmus may be exerted through the ophthalmic branch of the trigeminal nerve, which is part of the proprioceptive pathway [Dell'Osso 2002]. The use of prisms may be helpful in individuals with binocular vision whose nystagmus is dampened by convergence. There are no fixed age groups for which prisms are prescribed; however, prisms are typically used in adults, teenagers, and cooperative children.Pharmacologic. Memantine and gabapentin have been reported to improve visual acuity, intensity of nystagmus, and foveation [Shery et al 2006, McLean et al 2007].SurgeryThe Anderson-Kestenbaum procedure consists of surgery of the extraocular muscles to shift the null zone to the primary position. As mentioned above, the cause of an anomalous head posture is an eccentric null zone. Therefore, shifting the null zone also corrects the anomalous head posture. In practice this procedure not only shifts but also broadens the null zone, as well as decreasing nystagmus outside the null zone. Abnormal head posture is only seen in approximately 15% of affected individuals. Clinical trials to assess the role of horizontal rectus tenotomy and its effects on visual function found an improvement in nystagmus waveform and visual function [Hertle et al 2003].SurveillanceRegular follow up, especially during childhood, is necessary to evaluate for development of vision, refractive errors, strabismus, and/or ambylopia. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. FRMD7-Related Infantile Nystagmus: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNYS1FRMD7Xq26​.2FERM domain-containing protein 7FRMD7 @ LOVDFRMD7Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for FRMD7-Related Infantile Nystagmus (View All in OMIM) View in own window 300628FERM DOMAIN-CONTAINING PROTEIN 7; FRMD7 310700NYSTAGMUS 1, CONGENITAL, X-LINKED; NYS1Normal allelic variants. FRMD7 is approximately 51 kb in length and comprises 12 exons. The length of the mRNA transcript is 3.2 kb.Pathologic allelic variants. More than 40 different mutations have been reported [Tarpey et al 2006, Schorderet et al 2007, Self et al 2007, Zhang et al 2007a, Zhang et al 2007b, He et al 2008, Kaplan et al 2008, Li et al 2008, Thomas et al 2011a]. The pathologic allelic variants are spread throughout the gene and consist of missense, nonsense, and splice-site mutations and frameshift deletions and insertions. Fingert et al [2010] reported the identification of an FRMD7 deletion involving exons 2, 3, and 4 in affected males from a large three-generation family with X-linked infantile nystagmus.Normal gene product. The normal gene product consists of 714 amino acids with two functional domains, B41 and FERM-C. In situ hybridization experiments in human embryonic brain (~37 days post-ovulation) have shown that the expression of FRMD7 is restricted to the mid- and hindbrain, regions known to be involved in motor control of eye movement [Tarpey et al 2006]. High-resolution spatial and temporal expression studies have shown that FRMD7 is expressed within the developing optokinetic and vestibulo-ocular reflex arcs [Thomas et al 2011a]. Subcellular localization of FRMD7 was restricted to the neuronal cell body, the primary dendrite extension and the distal tip of the growth cone in dendrites [Betts-Henderson et al 2010]. Abnormal gene product. Knockdown assays of FRMD7 in Neuro2A cells show altered neurite outgrowth as a result of retinotoic acid-induced differentiation [Betts-Henderson et al 2010]. In Neuro2A cells no difference was seen between the subcellular localization of the mutant FRMD7 protein resulting from c.781C>G and c.886G>C missense mutations and wild type. However, nuclear localization was observed with the mutant protein resulting from a c.1003C>T nonsense mutation. This suggests that the C-terminus may play a role in the subcellular localization of the FRMD7 protein [Pu et al 2011].