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.

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.

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

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).

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.

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].

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.

Mode of Inheritance

By definition, X-linked congenital stationary night blindness (CSNB) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have X-linked CSNB nor will he be hemizygous for the CACNA1F or NYX pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected male, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the CACNA1F or NYX pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo CACNA1F or NYX pathogenic variant, in which case the mother is not a carrier.
• If the proband is female and has biallelic pathogenic variants (rare), both the mother and the father may have X-linked CSNB-causing pathogenic variants (i.e., the mother may be a carrier and the father may be affected) [Bech-Hansen et al 1998].

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an CACNA1F or NYX pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygous and will usually not be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the CACNA1F or NYX pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males transmit the X-linked CSNB-causing pathogenic variant to:

• All of their daughters, who will be heterozygous and will usually not be affected;
• None of their sons.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the pathogenic variant, and the aunts' offspring, depending on their sex, may be at risk of being carriers or of being affected.

Carrier (Heterozygote) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected. (2) Identification of female heterozygotes requires either (a) prior identification of the CACNA1F or NYX pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 increased risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the CACNA1F or NYX pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for X-linked CSNB are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Genes associated with X-linked congenital stationary night blindness (X-linked CSNB) encode proteins that are specifically expressed in the retina: nyctalopin and voltage-dependent L-type calcium channel subunit alpha-1F (Ca_v1.4/α_1F) for complete and incomplete CSNB, respectively. Pathogenic variants identified in these genes impinge on synaptic transmission from photoreceptors (rods and cones) to inner retinal cells.

Pathogenic variants in NYX are predicted to cause defects in nyctalopin, including alterations in its conformation, loss of the GPI anchor, and deletions of a portion or all of the protein [Zeitz 2007].

Expression studies have shown that some (not all) CACNA1F pathogenic missense variants alter the channel activation properties of the Ca_v1.4 calcium channel [McRory et al 2004, Hemara-Wahanui et al 2005, Hoda et al 2005]; other missense variants may affect the assembly or expression of the presynaptic ribbon complex [Hoda et al 2006]. Pathogenic nonsense and frameshift variants are predicted to cause loss of channel function or/and photoreceptor synapses.

Mechanism of disease causation. Loss of function

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Acknowledgments

The authors would like to thank Linda MacLaren and Karen McElligott for years of service to the Mennonite community affected with CSNB2A.

Author History

N Torben Bech-Hansen, PhD; University of Calgary (2007-2012)
Kym M Boycott, PhD, MD; University of Ottawa, Canada (2007-2019)
Stephanie Hoang, MSc (2019-present)
Ian M MacDonald, MD, CM (2007-present)
Yves Sauvé, PhD; University of Alberta (2007-2019)
Sari Tuupanen, PhD (2019-present)

Revision History

• 3 July 2019 (sw) Comprehensive update posted live
• 26 April 2012 (me) Comprehensive update posted live
• 16 January 2008 (me) Review posted live
• 9 August 2007 (im) Original submission