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FRMD7-Related Infantile Nystagmus

Synonyms: NYS1, X-Linked Idiopathic Infantile Nystagmus

, BSc (Hons), MBChB, PhD, , MRCOphth, , MRCS, MRCOphth, , BSc, MSc, PhD, and , MD, Univ Doz, FRCOphth.

Author Information
, BSc (Hons), MBChB, PhD
Academic Foundation Doctor, Ophthalmology Group
University of Leicester
Leicester, United Kingdom
, MRCOphth
Clinical Lecturer, Ophthalmology Group
University of Leicester
Leicester, United Kingdom
, MRCS, MRCOphth
Clinical Research Fellow, Ophthalmology Group
University of Leicester
Leicester, United Kingdom
, BSc, MSc, PhD
Lecturer, Ophthalmology Group
University of Leicester
Leicester, United Kingdom
, MD, Univ Doz, FRCOphth
Professor of Ophthalmology, Ophthamology Group
University of Leicester
Leicester, United Kingdom

Initial Posting: ; Last Update: September 29, 2011.

Summary

Disease 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, such as visual evoked potential (VEP) and electroretinogram (ERG), 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) and molecular genetic testing of FRMD7.

Management. Treatment of manifestations: Routine correction of refractive errors; contact lenses that correct refractive errors may also dampen the intensity of the nystagmus. Prisms may be useful in those with binocular vision whose nystagmus is dampened by convergence. Memantine and gabapentin can improve intensity of nystagmus, foveation, and, hence, visual acuity. Surgical approaches include: horizontal rectus tenotomy to improve the waveform of the nystagmus and visual function and 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.

Surveillance: Routine monitoring, especially during childhood, to evaluate visual acuity and development of refractive errors, strabismus, and/or ambylopia.

Genetic counseling. FIN is inherited in an X-linked manner. Affected males transmit the disease-causing mutation to all of their daughters and none of their sons. Women who are carriers have a 50% chance of transmitting the mutation in each pregnancy. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible once the disease-causing mutation has been identified in the family.

Diagnosis

Clinical 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 oscillations
  • Amplitude 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 vision
  • Family history of nystagmus consistent with X-linked inheritance

Findings 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 tests
    • Electroretinogram (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

Table 1. Summary of Molecular Genetic Testing Used in FRMD7-Related Infantile Nystagmus

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
FRMD7Sequence analysis of exons and splice sites Sequence variants 4,583%-94% 5,6
Deletion/duplication analysis 7(Multi)exonic or whole-gene deletion Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. 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.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic 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 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.

6. 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; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To 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 vision
  • Strabismus
  • Binocularity
  • Ocular motility
  • Head posture

This should be supplemented by detailed ophthalmic examination and electrodiagnostic investigations including:

  • Slit-lamp examination
  • Fundus examination
  • Measurement of refractive error
  • VEPs
  • ERG

Note: (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.

Clinical Description

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):

Figure 1

Figure

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 (more...)

Figure 2

Figure

Figure 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...)

  • 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 1No nystagmus
7 weeksSquare wave jerk
8 weeksSmall pendular nystagmus
10 weeksLarge jerk type nystagmus
14 weeksSmall pendular nystagmus
7-12 monthsConjugate 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 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 Correlations

Studies 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].

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].

Anticipation

Anticipation does not occur in FIN.

Nomenclature

FRMD7-related infantile nystagmus (FIN) is a subcategory of idiopathic infantile nystagmus (IIN).

Congenital motor nystagmus is an outdated term for FIN.

Prevalence

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.

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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations 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 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

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. 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].

Surgery

  • The 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].

Surveillance

Regular follow up, especially during childhood, is necessary to evaluate for development of vision, refractive errors, strabismus, and/or ambylopia.

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 for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

FRMD7-related infantile nystagmus is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

Parents of a female proband

  • A female with FRMD7-related infantile nystagmus may have inherited the mutation from either her mother or her father.
  • A female proband with FRMD7-related infantile nystagmus may have the disorder as the result of a new mutation. The proportion of cases caused by de novo mutations is unknown.

Sibs of a male proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation may or may not have nystagmus.
  • If the mother of a simplex case is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Sibs of a female proband

  • The risk to the sibs of a female proband depends on the genetic status of the parents.
  • If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation may or may not have nystagmus.
  • If the father of the proband has a disease-causing mutation, he will transmit the mutation to all of his daughters and none of his sons.

Offspring of a male proband. Males will transmit the disease-causing mutation to all of their daughters and none of their sons.

Offspring of a female proband. With each pregnancy, the chance that a heterozygous female will transmit the disease-causing mutation is 50%. Sons who inherit the mutation will be affected; daughters who inherit the mutation may or may not have nystagmus.

Other family members of the proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has the mutation, his or her family members may be at risk.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation in the family has been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements

Requests for prenatal testing for conditions such as FIN are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Nystagmus Network
    303-D Beltline Place
    #321
    Decatur AL 35603
    Email: LGlaude@nystagmus.org
  • Nystagmus Network
    Provides patient information, support and scientific research for nystagmus in Europe
    13 Tinsley Close
    Newark Nottinghamshire NG23 5BS
    United Kingdom
    Phone: 0845 634 2630; 01636 627 004
    Email: info@nystagmusnet.org
  • Medline Plus

Molecular Genetics

Information 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 Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
NYS1FRMD7Xq26​.2FERM domain-containing protein 7FRMD7 @ LOVDFRMD7

Data 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)

300628FERM DOMAIN-CONTAINING PROTEIN 7; FRMD7
310700NYSTAGMUS 1, CONGENITAL, X-LINKED; NYS1

Normal 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].

References

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Literature Cited

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Chapter Notes

Acknowledgments

The authors would like to acknowledge the Ulverscroft Foundation and the National Eye Research Centre for their continued support towards research into FRMD7-related infantile nystagmus.

Revision History

  • 29 September 2011 (me) Comprehensive update posted live
  • 12 February 2009 (me) Review posted live
  • 8 October 2008 (ig) Original submission
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