Frmd7-Related Infantile Nystagmus
Summary
Clinical characteristics.
FRMD7-related infantile nystagmus (FIN) is characterized by either the onset of horizontal, conjugate, gaze-dependent nystagmus in the first six months of life or periodic alternating nystagmus (with cyclical changes of nystagmus direction) of infantile onset. Binocular vision and color vision are normal and visual acuity is typically better than 6/12. An abnormal head posture is seen in approximately 15% of affected individuals. The eyes are structurally normal and electrophysiologic studies (e.g., visual evoked potential, electroretinogram) are normal. Affected females report slightly better visual acuity than affected males; however, no differences between males and females in the amplitude, frequency, and waveform of nystagmus are observed.
Diagnosis/testing.
The diagnosis is based on clinical findings (including, when possible, ocular motility recordings). Identification of a hemizygous (in a male proband) or heterozygous (in a female proband) pathogenic variant in FRMD7 by molecular genetic testing can establish the diagnosis if clinical features are inconclusive.
Management.
Treatment of manifestations: Correction of refractive errors as early as possible. Prisms may be useful in those with binocular vision whose nystagmus is dampened by convergence. Memantine and gabapentin can improve visual acuity, intensity of nystagmus, and foveation. Surgical approaches include: the Anderson-Kestenbaum procedure (surgery of the extraocular muscles to shift the null zone to the primary position) in order to correct anomalous head posture and horizontal rectus tenotomy to improve the waveform of the nystagmus and visual function.
Surveillance: Regular monitoring, especially during childhood, to evaluate visual acuity and development of refractive errors, strabismus, and/or amblyopia.
Genetic counseling.
FIN is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Women who are carriers have a 50% chance of transmitting the pathogenic variant in each pregnancy. Carrier testing for at-risk female relatives and prenatal testing for a pregnancy at increased risk are possible once the pathogenic variant has been identified in the family.
Diagnosis
Currently there are no formal diagnostic clinical criteria for FRMD7-related infantile nystagmus.
Suggestive Findings
The diagnosis of FRMD7-related infantile nystagmus (FIN) should be suspected in an individual with the following findings [Thomas et al 2008].
Clinical findings
- Onset of nystagmus during infancy (age ≤6 months)
- Horizontal and conjugate nystagmus oscillations
- Visual acuity that is typically better than 0.3 LogMAR (Snellen equivalent 6/12)
- Good binocular vision and normal color vision
- Family history of nystagmus consistent with X-linked inheritance
- In some individuals: dampening of the nystagmus by convergence
- Less common findings: anomalous head posture (15% of affected individuals) and strabismus (8% of affected individuals)
Optical coherence tomography. Normal foveal morphology on optical coherence tomography or (less commonly) Grade 1 foveal hypoplasia [Thomas et al 2014]
Eye movement recordings
- 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 of nystagmus can be gaze dependent (i.e., small amplitude on central gaze when compared to left and right gaze).
- Amplitude and direction of the quick phase may be time dependent (periodic alternating nystagmus) [Thomas et al 2011].
Other evaluations. The following are normal in individuals with FIN:
- Slit-lamp biomicroscopy (normal iris pigmentation with no iris transillumination)
- Fundoscopy
- Cranial MRI
- Electroretinogram
- Visual evoked potentials
Establishing the Diagnosis
Male proband. The diagnosis of FRMD7-related infantile nystagmus (FIN) is suspected in a male proband with the above Suggestive Findings. Diagnosis is established by identification of a hemizygous pathogenic variant in FRMD7 by molecular genetic testing (see Table 1).
Female proband. The diagnosis of FIN is suspected in a female proband with the above Suggestive Findings. Diagnosis is established by identification of a heterozygous pathogenic variant in FRMD7 by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FIN is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of FIN has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic findings suggest the diagnosis of FIN molecular genetic testing approaches can include single-gene testing, or use of a multigene panel:
- Single-gene testing. Sequence analysis of FRMD7 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes FRMD7 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of FIN is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in FRMD7-Related Infantile Nystagmus
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method 3 |
|---|---|---|
| FRMD7 | Sequence analysis 4, 5 | 83%-94% 5, 6 (familial cases) 0%-29% 5, 6 (simplex cases) |
| Gene-targeted deletion/duplication analysis 7 | 3 families 8 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Includes males and heterozygous females
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 6.
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 [2011], Choi et al [2018]
- 7.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 8.
Fingert et al [2010], AlMoallem et al [2015], Thomas et al [2017]
Clinical Characteristics
Clinical Description
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) [Thomas et al 2008, Thomas et al 2011].
Nystagmus waveform characteristics are established by eye movement recordings that assess the following (see Figure 1 and Figure 2):
Figure 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 plane. (more...)
Figure 2.
The horizontal eye movement recordings in an individual with FIN (a) Gaze-dependent nystagmus. Note the right-beating pattern on right gaze.
- Conjugacy
- Plane 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:
- Frequency
- Amplitude
- Foveation 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 Example
| Age | Waveform Description |
|---|---|
| 5 weeks 1 | No nystagmus |
| 7 weeks | Square wave jerk |
| 8 weeks | Small pendular nystagmus |
| 10 weeks | Large jerk type nystagmus |
| 14 weeks | Small pendular nystagmus |
| 7-12 months | Conjugate pendular nystagmus |
Gottlob [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 idiopathic 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 >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.
The optokinetic response (OKR) is abnormal, with either low gains or reversal patterns described [Thomas et al 2008]. In individuals with periodic alternating nystagmus and a FRMD7 pathogenic variant no OKR is observed [Thomas et al 2008, Thomas et al 2011]. In unaffected female carriers a subnormal OKR has been described [Thomas et al 2008].
Optical coherence tomography studies have shown either normal fovea morphology or grade 1 foveal hypoplasia [Thomas et al 2014]. Similarly, optic nerve morphology can be abnormal in FIN [Thomas et al 2014, Choi et al 2018].
Genotype-Phenotype Correlations
Studies have shown extensive intra- and interfamilial variability in the phenotype [Self et al 2007, Shiels et al 2007, Thomas et al 2008].
FIN with periodic alternating nystagmus is predominantly associated with FRMD7 pathogenic missense variants [Thomas et al 2011].
Penetrance
Penetrance of FRMD7-related infantile nystagmus (FIN) is full in males and approximately 50% in females; however, eye movement recordings of clinically unaffected females can on occasion reveal a subclinical form of nystagmus [Tarpey et al 2006, Thomas et al 2008]. Analysis of eye movements to an optokinetic stimulus may show a poor response in some clinically unaffected females [Thomas et al 2008].
Nomenclature
Idiopathic infantile nystagmus (IIN) is a term used to describe nystagmus which presents at birth or infancy. There are no associated afferent or brain defects and IIN is characterized by normal electroretinograms and visual evoked potentials. If an FRMD7 pathogenic variant is identified it should be termed FRMD7-related infantile nystagmus (FIN).
Congenital motor nystagmus is an outdated term for IIN.
Infantile nystagmus syndrome (INS) is an umbrella term used to describe different forms of infantile nystagmus (with or without sensory defects) characterized by an increasing slow phase velocity.
Prevalence
The prevalence of IIN is estimated at 2:10,000 [Sarvananthan et al 2009]. Therefore, the prevalence of FIN is lower than 2:10,000.
Differential Diagnosis
The 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. Using eye movement recordings one can determine whether there is a periodic component to the nystagmus, which would suggest the presence of periodic alternating nystagmus.
Idiopathic infantile nystagmus (IIN) is characterized by infantile nystagmus and reduced visual acuity in individuals without an identified molecular cause. It is not associated with any other sensory pathologies. Color vision, slit-lamp examination, electroretinogram, and visual evoked potential are normal. Strabismus is uncommon (~10% of affected individuals). Eye movement recordings show conjugate horizontal oscillations with an increasing slow phase velocity. IIN is similar to FIN; however, some of the distinguishing signs can 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.
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]. See Congenital Nystagmus OMIM Phenotypic Series to view loci thought to be associated with this phenotype in OMIM.
Table 3.
Disorders to Consider in the Differential Diagnosis of FRMD7-Related Infantile Nystagmus (FIN)
| DiffDx Disorder | Gene(s) | MOI | Clinical Features of DiffDx Disorder | ||
|---|---|---|---|---|---|
| Overlapping w/FIN | Distinguishing from FIN 1 | ||||
| Oculocutaneous albinism (OCA) 2 | OCA1 (OMIM 203100, 606952) OCA2 (OMIM 203200) OCA3 (OMIM 203290) OCA4 | TYR OCA2 TYRP1 SLC45A2 | AR | Infantile nystagmus | In OCA:
|
| X-linked ocular albinism | GPR143 | XL |
| ||
| Chediak-Higashi syndrome (CHS) | LYST | AR | Infantile nystagmus | In CHS:
| |
| Achromatopsia | AFT6 CNGA3 CNGB3 GNAT2 PDE6C PDE6H | AR | Infantile nystagmus (pendular or jerk nystagmus in achromatopsia) | In achromatopsia:
| |
| Blue cone monochromatism (OMIM 303700) | OPN1LW OPN1MW | XL | Infantile nystagmus | In blue cone monochromatism:
| |
| X-linked congenital stationary night blindness (CSNB1 and CSNB2) | CACNA1F NYX | XL |
| In CSNB:
| |
| Leber congenital amaurosis (LCA) | See footnote 4. | AR (AD) | Infantile nystagmus | In LCA 5:
| |
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked
- 1.
Bolded text indicates key distinguishing features.
- 2.
All forms of albinism are characterized by infantile nystagmus. The most common forms of albinism are OCA and X-linked ocular albinism.
- 3.
When color vision is difficult to test in young children, ERG can be used.
- 4.
Pathogenic variants in at least 17 genes are known to cause LCA (see Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview).
- 5.
LCA is a severe dystrophy of the retina typically evident in 1st year of life.
- 6.
Because measuring visual acuity in infants can be difficult, ERG is the test of choice for distinguishing between FIN and LCA in infants.
Other conditions to consider. 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].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with FRMD7-related infantile nystagmus (FIN), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
- Evaluation of visual acuity at different gaze positions
- Recording eye movements to evaluate the nystagmus waveform:
- Amplitude, frequency, and conjugacy
- Foveation dynamics
- Null point width determination
- In individuals with periodic alternating nystagmus, recording of cycle duration and the presence of an alternating head posture
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Optical devices
- Correction of refractive errors as early as possible using contact lenses or appropriate refractive correction can improve visual acuity appreciably. Previously it was thought that contact lenses also had 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]. Recent work by Jayaramachandran et al [2014] suggest that contact lens wear does not significantly improve nystagmus or visual acuity compared to spectacle wear.
- 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].
Surgery. The Anderson-Kestenbaum procedure consists of surgery of the extraocular muscles to shift the null zone to the primary position. As mentioned in Clinical Description, 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.
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].
Surveillance
Regular follow up, especially during childhood, is necessary to evaluate for development of vision, refractive errors, strabismus, and/or amblyopia.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.