FRMD7-Related Infantile Nystagmus - Gene Reviews - NCBI Bookshelf

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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews [Internet]. Seattle (WA): University of

Washington, Seattle; 1993-.

Bookshelf ID: NBK3822 PMID: 20301748

FRMD7-Related Infantile Nystagmus

Synonyms: NYS1, X-Linked Idiopathic Infantile Nystagmus

Mervyn G Thomas, BSc (Hons)PhD Candidate

Ophthalmology Group

University of Leicester

Leicester, United Kingdom

[email protected]

Shery Thomas, MRCOphthClinical Lecturer

Ophthalmology Group



[email protected]

Anil Kumar, MRCS, MRCOphth

Clinical Research FellowOphthalmology Group


Frank A Proudlock, BSc, MSc, PhDSenior Lecturer

Ophthalmology Group



Irene Gottlob, MD, Univ Doz, FRCOphthProfessor of Ophthalmology

Ophthamology Group



[email protected]

Initial Posting: February 12, 2009.

Summary

Disease characteristics.FRMD7-related infantile nystagmus (FIN) is characterized by the onset of

horizontal, conjugate, gaze-dependent nystagmus in the first six months of life. 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 ofFRMD7(currently available on a research basis only).

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

D7-Related Infantile Nystagmus - GeneReviews - NCBI Bookshelf http://www.ncbi.nlm.nih.gov/books/N

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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. No laboratories offering molecular genetic testing for prenatal

diagnosis of FIN are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available

through laboratories offering custom prenatal testing for families in which the disease-causing mutation has

been identified.

Diagnosis

Clinical Diagnosis

The diagnosis ofFRMD7-related infantile nystagmus (FIN) should be considered in an individual with the

following findings [Thomas et al 2008].

Note: Although these are the typical findings 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 (a) the nystagmus waveform characteristics

including conjugacy, direction of oscillations (quick phase), pattern of oscillations (pendular, jerk, orbidirectional waveforms), and plane of oscillations (horizontal, vertical, and torsional) and (b)

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.

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) is the only gene known to be associated with FIN [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].

Clinical testing is not available.

Research testing


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Sequence analysis. Once a clinical diagnosis of FIN is suspected (see Clinical Diagnosis) sequence

analysis can be used to confirm mutations ofFRMD7.

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

Gene

SymbolTest Method Mutations Detected

Mutation Detection

Frequency by Test

Method1

Test

Availability

FRMD7

Sequence analysis ofexons and splice

sites2

Missense, nonsense,splice-site, frameshift, and

silent mutations

83%-94%Research

only

Mutation scanning3 Frameshift and splice-site

mutations~20%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as

clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a

non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's

licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Percent of disease alleles detected in individuals with a phenotype characteristic of FIN and a positive family history

2. Method described in Tarpey et al [2006] and Schorderet et al [2007]

3. Method described in Self et al [2007]

Testing Strategy

Confirming/establishing 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 that the diagnosis is idiopathic infantile nystagmus (IIN). In addition to the above findings, a family

history of X-linked inheritance strongly suggests the diagnosis of FIN. However, 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 tests carried out on these individuals are primarily 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 such as ocular motility recordings can be

performed. (2) Clinical confirmation of mutations identified in a research laboratory may be available for

families in which a disease-causing mutation has been identified in a research laboratory. See .


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Genetically Related (Allelic) Disorders

No other phenotype is known to be associated with mutations in FRMD7.

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 waveform characteristics are established by eye movement recordings that assess the following

(see Figure 1 and Figure 2):

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

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


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and development of foveation (period during which the eyes remain relatively still and the image is incident on

the fovea). 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 weeks1 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 FIN than with non- FRMD7IIN [Thomas et

al 2008]. These oscillations are accentuated by attention, anxiety, attempts to fixate on an object, anddirecting 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 ones 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.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Studies have shown extensive intra- and interfamilial variability in the phenotype [Self et al 2007, Shiels et al

2007, Thomas et al 2008].

Penetrance

Penetrance of 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

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


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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 less

than 2:10,000.

Differential Diagnosis

For current information on availabil ity of genetic testing for disorders included in this section, see GeneTests

Laboratory Directory. ED.

The diagnosis ofFRMD7-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.

Because of the current unavailability of clinical genetic testing, 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-FRMD7IIN.

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. Although non-FRMD7IIN is similar to FIN, distinguishing signs include:(1) abnormal head posture and eccentric null zone; (2) amplitude of the nystagmus that is not as significantly

dependent on gaze as in FIN; and (3) pendular waveform that is not as commonly encountered as in FIN.

The cause of non-FRMD7IIN is unknown. Affected individuals rarely have a family history of nystagmus;

however, in some rare cases autosomal dominant inheritance has been reported [Klein et al 1998, Kerrison et

al 1999, Hoffmann et al 2004].

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 are present plus reduced pigmentation

of the skin and hair. 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

MATP). Inheritance is autosomal recessive in these four types.

X-linked ocular albinism is caused by mutations in OA1. Similaties 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 andchildren 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 known to be associated with 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. The normal color vision observed in FIN can distinguish between the


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two conditions. When color vision is difficult to test in young children, ERG can be used. Mutations of the

genes CNGB3, CNGA3, and GNAT2are 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 (but 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.

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 NYXmutations, and CSNB2, caused by CACNA1Fmutations. Individuals w ith complete X-linked CSNB (CSNB1)

generally report severe night blindnes whereas individuals with incomplete X-linked CSNB (CSNB2) do not

uniformly report severe night blindness. Scotopic ERG shows severly 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 oculo-digital 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. Eight genes have been reported to be associated withLCA. 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].

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

Treatment of Manifestations

Optical devices

Correction of refractive errors as early as possible using contact lenses or appropriate refractivecorrection 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 pr isms may be useful 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].


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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, carried out to asses 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.

Testing 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding

the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as

information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder.

These organizations have been established for individuals and families to provide information, support, and

contact with other affected individuals.

Genetic Counseling

Genetic counseling is the process of providing individuals and fami lies 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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Mode of Inheritance

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

Risk to Family Members

This section is written from the perspective that molecular genetic testing for this disorder is available on a

research basis only and results should not be used for clinical purposes. This perspective may not apply to

families usingcustom mutation analysis. ED.

Parents of a male proband

The father of an affected male will not have the disease nor will he be a carrier of the mutation.

In a family with more than one affected individual, the mother of an affected male is an obligate

carrier.

If pedigree analysis reveals that the proband is the only affected family member, the mother may be a

carrier or the affected male may have a de novogene mutation, in which case the mother is not a

carrier.


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When an affected male is the only affected individual in the family several possibilities regarding his

mother's carrier status need to be considered:

He has a de novodisease-causing mutation in FRMD7and his mother is not a carrier

His mother has a de novodisease-causing mutation in FRMD7, either (a) as a "germline

mutation" (i.e., present at the time of her conception and therefore in every cell of her body);

or (b) as "germline mosaicism" (i.e., present in some of her germ cells only)

His mother has a disease-causing mutation that she inherited from a maternal female

ancestor.

Parents of a female proband

A female with FIN may have inherited the mutation from either her mother or her father.

A female proband with FIN may have the disorder as the result of a new gene mutation. The

proportion of cases caused by de novomutations 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 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 may be available from laboratories offering clinical

testing/confirmation of mutations identified previously if the mutation has been identified in the family. See

.

Related Genetic Counseling Issues

Family planning

The optimal time for determination of genetic risk 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. See for

a list of laboratories offering DNA banking.


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Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of FIN are listed in the GeneTests

Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing

mutation has been identified. For laboratories offering custom prenatal testing, see .

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 available for families in which the disease-causing

mutation has been identified. For laboratories offering PGD, see .

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

Name

Gene

Symbol

Chromosomal

Locus

Protein Name Locus Specific HGMD

NYS1 FRMD7 Xq26.2 FERM domain-containing

protein 7

FRMD7 @

LOVD

FRMD7

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)

linked to, click here.

Table B. OMIM Entries for FRMD7-Related Infantile Nystagmus (View All in OMIM)

300628 FERM DOMAIN-CONTAINING 7; FRMD7

310700 NYSTAGMUS 1, CONGENITAL, X-LINKED; NYS1

Normal allelic variants.FRMD7is approximately 51 kb in length and consists of 12 exons. The length of the

mRNA transcript is 3.2 kb.

Pathologic allelic variants. More than 35 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]. The pathologic allelic variants are spread throughout the gene and consist of missense,

nonsense, and splice-site mutations and frameshift deletions and insertions.

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 ofFRMD7is restricted to the mid- and hindbrain, regions known to be involved in

motor control of eye movement [Tarpey et al 2006].

Abnormal gene product. The functional role of the FERM domain-containing protein 7 (FRMD7) protein is

unknown; however, it may have a role in modulating the length and degree of branching of neurites based on

the close amino acid sequence homology to the protein products ofFARP1 and FARP2. Therefore, an

abnormal FRMD7 protein may alter neurite development in the midbrain, cerebellum, and retina [Kubo et al

2002, Toyofuku et al 2005, Tarpey et al 2006]. It has been suggested that the disorder seen in FIN is as a

result of null mutations, resulting in a complete absence of the FRMD7 protein.

Resources

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder.

These organizations have been established for individuals and families to provide information, support, and


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contact with other affected individuals. GeneTests provides information about selected organizations and

resources for the benefit of the reader; GeneTests is not responsible for information provided by other

organizations.ED.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the

PubMed Clinical Queries page

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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

12 February 2009 (me) Review posted live

8 October 2008 (ig) Original submission


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Figures

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.


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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 the foveation period.

(c) The intensity of nystagmus calculated using amplitude and frequency

(d) Conjugate oscillations

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