X-Linked Congenital Stationary Night Blindness

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Summary

Clinical characteristics.

X-linked congenital stationary night blindness (CSNB) is characterized by non-progressive retinal findings of reduced visual acuity ranging from 20/30 to 20/200; defective dark adaptation; refractive error, most typically myopia ranging from low (-0.25 diopters [D] to -4.75 D) to high (≥-10.00 D) but occasionally hyperopia; nystagmus; strabismus; normal color vision; and normal fundus examination. Characteristic ERG findings can help distinguish between complete X-linked CSNB and incomplete X-linked CSNB.

Diagnosis/testing.

The diagnosis of X-linked CSNB is established in a male proband with characteristic clinical and electroretinogram (ERG) findings and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic variant in CACNA1F or NYX by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive. The diagnosis of X-linked CSNB may be established in a female proband with ERG findings suggestive of X-linked CSNB and identification of a heterozygous or biallelic pathogenic variant in CACNA1F or NYX by molecular genetic testing.

Management.

Treatment of manifestations: Glasses or contact lenses to treat refractive error (myopia or hyperopia); conventional strabismus surgery may be required to improve binocularity or head posture.

Surveillance: At a young age yearly eye examinations with refraction to identify and treat myopia as early as possible.

Agents/circumstances to avoid: Reduced visual acuity and difficulties seeing at night may preclude driving a car or restrict the class of driving license.

Genetic counseling.

By definition, X-linked CSNB is inherited in an X-linked manner. The father of an affected male will not have X-linked CSNB nor will he be hemizygous for the pathogenic variant. If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Males with X-linked CSNB will pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible for families in which the pathogenic variant has been identified.

Diagnosis

Suggestive Findings

Males. X-linked congenital stationary night blindness (CSNB) should be suspected in a male proband with the following characteristic clinical and electroretinogram (ERG) findings characteristicec of complete X-linked CSNB or incomplete X-linked CSNB (see Table 1):

Characteristic clinical findings:

  • Reduced visual acuity
  • Night blindness
  • Myopia
  • Nystagmus (not universal) and strabismus (50%-70%)
  • Normal color vision
  • Normal fundus examination
  • Family history consistent with X-linked inheritance

Characteristic findings on ERG examination:

  • ERG is used to assess the changes in electrical activity of the retina in response to light. The b-wave is caused by the depolarization of ON bipolar cells in response to light stimuli and is strictly dependent on synaptic transmission from photoreceptors to ON bipolar cells.
  • Individuals with X-linked CSNB have reduced scotopic b-wave amplitudes in response to bright flashes after dark adaptation (Figure 1). The resulting ERG waveform is essentially a negative wave (amplitude of the a-wave is larger than the b-wave, not reaching the baseline) [Miyake et al 1986], referred to as the Schubert-Bornschein form [Schubert & Bornschein 1952].
  • The ERG can define specific retinal dysfunctions and, in general, differentiate the forms of X-linked CSNB (Table 1), thereby identifying the gene most likely to be involved (see Establishing the Diagnosis).
Figure 1.

Figure 1.

Representative full-field ERGs recorded from three males: A. Age 35 years, unaffected

Table 1.

Electroretinogram Findings in Complete and Incomplete X-Linked Congenital Stationary Night Blindness

ERG FindingComplete (NYX X-linked CSNB)Incomplete (CACNA1F X-linked CSNB)
Scotopic rod b-waveSeverely reduced or absentReduced
Mixed scotopic a-waveNormalSlightly reduced
Mixed scotopic b-waveReducedReduced
Scotopic OPAbsentSlightly reduced
Photopic a-waveNormal, slightly reduced, sawtooth (square) shapedReduced
Photopic b-waveSlightly reducedReduced
Photopic OPLost, except for OP4All OPs are lost.
30-Hz flickerNormal / slightly reducedReduced w/double peak

OP = oscillatory potential

Note: Pupillary responses have been described in the literature and in textbooks as "paradoxic" (i.e., miosis of pupils when lights are turned off, as opposed to dilation). This description predates genotyping. In 17 individuals with incomplete X-linked CSNB ages five to 51 years examined by one of the authors, none clearly demonstrated a paradoxic pupillary response. Further clarification of the presence or absence of this phenomenon in individuals with X-linked CSNB may require measurement with pupillometry.

Heterozygous females. X-linked CSNB should be suspected in a female proband with the following ERG findings (observed in some heterozygous females):

  • Reduced oscillatory potentials (OPs) associated with rod activity [Rigaudière et al 2003]
  • Reduced b-wave amplitudes (with unaffected OPs) in one heterozygous female [Rigaudière et al 2003]

Establishing the Diagnosis

Male proband. The diagnosis of X-linked CSNB is established in a male proband with the characteristic clinical and ERG findings described in Suggestive Findings and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic variant in CACNA1F or NYX by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive (see Table 2).

Female proband. The diagnosis of X-linked CSNB may be established in a female proband with ERG findings suggestive of X-linked CSNB and a heterozygous or biallelic pathogenic variant in CACNA1F or NYX identified by molecular genetic testing (see Table 2).

Molecular Genetic Testing

Approaches can include serial single-gene testing (recommended in individuals with a clear family history consistent with X-linked inheritance) or a multigene panel (recommended in individuals without a clear family history consistent with X-linked inheritance).

Serial single-gene testing. For individuals with a clear family history consistent with X-linked inheritance, ERG findings can be used to direct molecular genetic testing to the appropriate gene (see Table 1).

  • Sequence analysis of NYX should be performed first in individuals with ERG findings consistent with complete X-linked CSNB to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: 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.
  • Sequence analysis of CACNA1F should be performed first in individuals with ERG findings consistent with incomplete X-linked CSNB to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: 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.

Note: Targeted analysis for the CACNA1F founder variant c.3167_3168dupC can be performed first in individuals of Dutch-German Mennonite ancestry [Bech-Hansen et al 1998, Boycott et al 2000].

Multigene panel. For individuals without a clear family history consistent with X-linked inheritance, a CSNB multigene panel that includes CACNA1F, NYX, 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 2).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 2.

Molecular Genetic Testing Used in X-Linked Congenital Stationary Night Blindness

Gene 1, 2Proportion of X-Linked CSNB Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method
Sequence
analysis 4, 5		Gene-targeted deletion/duplication analysis 6
CACNA1F55% 7, 8>98% 7, 85 reported 9
NYX45% 7, 10>99% 7, 10, 114 reported 11
1.

Genes are listed in alphabetic order.

2.

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

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.

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.

7.

Zeitz [2007]

8.

Bijveld et al [2013], Zeitz et al [2015]

9.

Bijveld et al [2013], Hauke et al [2013], Zeitz et al [2015], Carss et al [2017]

10.

Bech-Hansen et al [2000], Pusch et al [2000]

11.

Pusch et al [2000], Bijveld et al [2013]

Clinical Characteristics

Clinical Description

X-linked congenital stationary night blindness (CSNB) is a congenital non-progressive retinal disorder characterized by defective night vision, reduced visual acuity, myopia, nystagmus, and strabismus that primarily affects males.

Males

Reduced visual acuity. Vision is reduced in all affected males in the range of 20/30 (6/9; log MAR 0.1) to 20/200 (6/60; log MAR 1.0).

Defective dark adaptation. Night blindness is a subjective finding. Individuals with NYX X-linked CSNB generally report severe night blindness. Individuals with CACNA1F X-linked CSNB do not uniformly report severe night blindness.

Myopia may range from low (-0.25 diopters [D] to -4.75 D) to high (≥ -10.00 D) [Boycott et al 2000, Allen et al 2003]. A few affected individuals have hyperopia.

Nystagmus and strabismus are reported in 50%-70% of affected individuals [Boycott et al 2000, Allen et al 2003]. Transient head posture with nystagmus was noted in the first two years of life in eight individuals with CACNA1F X-linked CSNB and one with NYX X-linked CSNB [Simonsz et al 2009].

In a large Mennonite cohort with incomplete (i.e., CACNA1F) X-linked CSNB, at least one of the following was not present in 72% of individuals: myopia, nystagmus, or night blindness [Boycott et al 2000].

Normal color vision is present in most individuals. Individuals with a severe X-linked CSNB may show mild color vision deficits.

Normal fundus examination is present in most individuals, although those with high myopia may show myopic degeneration.

Females

  • In general, heterozygous females do not exhibit clinical signs of X-linked CSNB.
  • Females who are homozygous for pathogenic variants in CACNA1F with features similar to those in males have been reported [Bech-Hansen et al 1998].

Phenotype Correlations by Gene

NYX pathogenic variants are associated with the complete form of X-linked CSNB (see Table 1) [Bech-Hansen et al 2000, Pusch et al 2000]. Individuals with NYX X-linked CSNB generally report severe night blindness.

CACNA1F pathogenic variants are associated with the incomplete form of X-linked CSNB [Bech-Hansen et al 1998, Strom et al 1998] (see Table 1). Individuals with CACNA1F X-linked CSNB do not uniformly report severe night blindness.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Penetrance

Penetrance of X-linked CSNB is probably 100%, but expressivity is variable [Boycott et al 2000]; individuals with mild presentations may be missed if electroretinography is not performed.

Nomenclature

X-linked CSNB has in the past been referred to as Schubert-Bornschein CSNB, which is a reference to the characteristic "negative" waveform (a-wave larger than the b-wave in response to a bright flash in the scotopic state) of the ERG seen in both X-linked forms of CSNB [Schubert & Bornschein 1952].

The terms "CSNB1" and "CSNB2" are sometimes used as abbreviations for complete and incomplete CSNB irrespective of the mode of inheritance; originally the terms referred to the two X-linked entities of CSNB.

Prevalence

The prevalence of X-linked CSNB is not known.

A CACNA1F founder variant, c.3166dupC (alias: c.3167_3168dupC), has been reported in individuals of Dutch-German Mennonite descent [Bech-Hansen et al 1998, Boycott et al 1998, Boycott et al 2000].

A common pathogenic variant in NYX, c.856delG, has been identified in Flemish individuals from Belgium [Leroy et al 2009].

A common founder variant in NYX, c.85_108del, has been identified in the United States [Bech-Hansen et al 2000].

Differential Diagnosis

Only a few conditions may initially be confused with the X-linked form of congenital stationary night blindness (CSNB).

Table 4.

Disorders to Consider in the Differential Diagnosis of X-Linked Congenital Stationary Night Blindness

Fundus 1DisorderGene(s)MOIClinical Features of Differential Diagnosis Disorder
Overlapping w/X-linked CSNBDistinguishing from X-linked CSNB
Normal fundusCSNB (non-X-linked)See footnote 2AR
AD		Most autosomal CSNB is clinically identical, w/exception of AD CSNB, Nougaret type.
  • Family history consistent w/X-linked inheritance may differentiate X-linked forms of CSNB from AD & AR forms.
  • In AD CSNB, Nougaret type (OMIM 610444) there is no significant refractive error & ERG waveform is Riggs type (not Schubert-Bornshein) 3 w/minimal a-wave in response to scotopic bright flash.
Blue cone monochromacy (OMIM 303700)OPN1LW
OPN1MW		XL
  • Poor vision
  • Nystagmus
  • Abnormal color vision
  • Almost completely abolished photopic ERG contrasting w/normal or minimally affected scotopic ERG
  • Fundus examination in young males is normal; some males develop macular atrophy in late adulthood.
FRMD7-related infantile nystagmusFRMD7XL
  • Poor vision
  • Nystagmus
  • Normal ERG
  • Normal VEP
  • Normal foveal contour
Abnormal fundusX-linked ocular albinismOA1XL
  • Poor vision
  • Nystagmus
  • Iris transillumination
  • Foveal hypoplasia
  • Heterozygous females have fundus signs (hypopigmentation of retinal pigment epithelium). 4
  • Absence of selective reduction in amplitude of b-wave on ERG
  • VEP responses show propensity for more crossing fibers than expected at level of chiasm.
X-linked juvenile retinoschisisRS1XL
  • Visual acuity reduced to same range seen in X-linked CSNB
  • Selective reduction in amplitude of b-wave on ERG
Fundus examination shows foveal schisis or foveal findings in virtually all affected males & ~50% have areas of peripheral retinoschisis.
Oguchi disease 5
(OMIM 258100, 613411)		SAG
GRK1		ARNon-progressiveFundus has abnormal color that becomes normal w/prolonged dark adaptation (Mizuo phenomenon). 6
Fundus albipunctatus 7
(OMIM 136880)		RDH5
RLBP1		AR
AD		Non-progressive
  • Fundus shows discretely scattered white retinal dots.
  • ERG, when recorded under standard conditions, shows selective reduction in b-wave that normalizes w/prolonged dark adaptation. 6

AD = autosomal dominant; AR = autosomal recessive; ERG = electroretinogram; MOI = mode of inheritance; VEP = visual evoked potential; XL = X-linked

1.

X-linked CSNB is characterized by a normal fundus.

2.

See Night blindness, congenital stationary: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

3.

Riggs [1954]

4.

Charles et al [1993]

5.

Oguchi disease is a form of CSNB reported in the Japanese.

6.

Dryja [2000]

7.

Fundus albipunctatus is a form of CSNB.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked congenital stationary night blindness (CSNB), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

  • Ophthalmologic examination
  • Electroretinography
  • Dark adaptation (optional)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Coincident high myopia or hyperopia can be managed with glasses or contact lenses.

Occasionally, a boy with X-linked CSNB may adopt a cosmetically unacceptable or functionally awkward head posture to dampen the degree of nystagmus in a particular position of gaze (the so-called "null point"). In some instances the position of gaze for the null point may be shifted to a better functional range by carefully planned strabismus surgery.

Surveillance

Regular (yearly) eye examinations are recommended with refraction at a young age to monitor for the development of myopia.

Agents/Circumstances to Avoid

Reduced visual acuity and difficulties seeing at night may preclude driving a car or restrict the class of driving license.

Evaluation of Relatives at Risk

For infants identified with high myopia, unusual head posture, or nystagmus and a family history of CSNB, ophthalmic examination and molecular genetic testing may confirm the diagnosis of CSNB, obviating the need for neuroimaging or clinical electrophysiologic testing under sedation or general anesthesia.

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 information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.