Congenital Stationary Night Blindness

Key Points at a Glance

Highlights of This Disease

• Congenital stationary night blindness (CSNB) is a congenital, non-progressive retinal dysfunction diagnosed by electroretinography (ERG) despite a nearly normal fundus.
• It is classified into two types: complete (cCSNB) and incomplete (iCSNB), with ERG findings being the definitive distinguishing feature.
• X-linked recessive inheritance is most common, with a higher prevalence in males. The causative gene for the complete type is NYX, and for the incomplete type, CACNA1F.
• The complete type presents with night blindness, nystagmus, and high myopia, while the incomplete type often does not involve complaints of night blindness.
• The negative-type ERG (marked reduction or loss of the b-wave under dark adaptation) is key to diagnosis. This test is essential for differentiating from amblyopia.
• There is no curative treatment; management focuses on refractive correction, genetic counseling, and regular follow-up.
• The condition is non-progressive and the prognosis is relatively good, but in rare cases with CACNA1F mutations, retinal and optic nerve atrophy may progress.

1. What is Congenital Stationary Night Blindness?

Congenital Stationary Night Blindness (CSNB) is a disease diagnosed by electroretinography (ERG) despite a nearly normal fundus. “Stationary” means the condition is non-progressive, and unlike progressive photoreceptor degeneration such as retinitis pigmentosa, it does not progress.

There are two types: complete CSNB (cCSNB) and incomplete CSNB (iCSNB). Clinical classification by ERG was performed before the causative genes were identified, and later genetic analysis proved that the clinical diagnoses at that time were genetically correct. This is a well-known example of the importance of clinical diagnosis.

Classic classification based on ERG findings includes the Schubert-Bornschein type (including cCSNB and iCSNB), which shows a negative-type ERG under dark adaptation, and the Riggs type, which reflects dysfunction of the rod photoreceptors themselves¹⁾.

CSNB is broadly classified into normal fundus type and abnormal fundus type. The normal fundus type includes Schubert-Bornschein type (complete and incomplete forms) and Riggs type, while the abnormal fundus type includes fundus albipunctatus and Oguchi disease. The genetic background is diverse, with 18 genes and over 360 mutations associated with CSNB ²⁾.

Complete cCSNB

Site of dysfunction: ON bipolar cells

ERG features: DA 0.01 shows absent b-wave. Negative-type ERG

Main causative genes: NYX (X-linked), GRM6, TRPM1, GPR179, LRIT3 (autosomal recessive)

Incomplete iCSNB

Site of dysfunction: ON/OFF bipolar cells

ERG features: DA 0.01 shows reduced but residual b-wave. Negative-type ERG.

Main causative genes: CACNA1F (X-linked), CABP4, CACNA2D4 (autosomal recessive)

Riggs-type CSNB

Site of dysfunction: Rod photoreceptors

ERG features: DA 3.0 shows reduced a-wave and b-wave amplitudes. LA normal.

Main causative genes: GNAT1, PDE6B, RHO, SLC24A1

Epidemiology

CSNB is classified as a rare inherited retinal disease. The prevalence in France is reported to be about 1/10,000 ²⁾. Because X-linked recessive inheritance is common, males are more frequently affected. Both complete and incomplete forms have also been reported with autosomal recessive inheritance.

History

Florent Cunier first described it in 1838. The Jean Nougaret family, traced over 11 generations and 56 individuals with night blindness, is considered the first detailed record¹⁾. Even before the genetic era, clinical classification using ERG had been established, giving this disease a historical background.

Q What does "stationary" mean?

A

It means that night blindness and visual impairment do not progress. Unlike retinitis pigmentosa, there is no degeneration or loss of photoreceptors. In most cases, both visual acuity and ERG remain unchanged over time. However, rare incomplete cases with CACNA1F gene mutations have been reported with slowly progressive retinal and optic nerve atrophy.

2. Main symptoms and clinical findings

Complete and incomplete types differ greatly in subjective symptoms and clinical findings. A comparison is shown below.

Complete Type (cCSNB)

Chief complaints: Night blindness (noticed from early childhood), decreased visual acuity, nystagmus

Refraction: Often accompanied by high myopia (median −7.4 D in reported cohorts)¹⁾

Fundus: In high myopia, tilted disc, temporal pallor of the optic disc, and chorioretinal atrophy may be observed.

Visual acuity: Ranges from 0.1 to 1.0, but mild reduction is common (median visual acuity logMAR 0.30, approximately 20/40)¹⁾

Nystagmus: Pendular nystagmus is frequently observed.

Incomplete form (iCSNB)

Chief complaint: Decreased visual acuity (rarely complains of night blindness)

Refraction: No consistent refractive tendency (cohort median −4.8 D)¹⁾

Fundus: No abnormalities

Visual acuity: Variable

Nystagmus: may be present

Color vision

Color vision is usually normal. In the complete type, blue sensitivity loss is observed in the peripheral area beyond 15 degrees on Blue on Yellow perimetry.

Photophobia

Photophobia (light sensitivity) is a common symptom in incomplete type³⁾. In CABP4-related diseases, night blindness is rare, and a tendency to prefer dark places (avoid bright light) is characteristic³⁾. Among children with iCSNB, only 54% present with night blindness as the main complaint, and most of the remaining are diagnosed with amblyopia or myopia⁷⁾.

Strabismus and Nystagmus

Esotropia is most commonly observed¹⁾. Nystagmus is pendular, high-frequency, low-amplitude, and non-conjugate¹⁾. Strabismus is present in 50–70% of cases²⁾.

OCT Findings

In some complete-type cases, optical coherence tomography (SD-OCT) has reported thinning of the inner nuclear layer (INL) ¹⁾. An association with high myopia has been suggested, but the mechanism has not been elucidated ¹⁾. In some patients, RNFL thinning and mGCC thinning have also been reported ²⁾. In CABP4-related diseases, foveal hypoplasia, ellipsoid zone disruption, foveal elevation, and subfoveal hyporeflective zone have been reported ³⁾.

Characteristic Findings of Fundus Abnormalities

• White dot retina: Yellow-white spots scattered from the posterior pole (excluding the macula) to the mid-periphery
• Oguchi disease: Mizuo-Nakamura phenomenon (after dark adaptation, the fundus appears normal, but after light exposure, the retina shows a golden metallic sheen)

Pitfall of normal fundus

In CSNB, patients present with poor vision and nystagmus from infancy, yet fundus findings are almost normal, making it easily misdiagnosed as amblyopia. If amblyopia treatment is ineffective or poor vision does not improve despite a normal fundus, ERG testing with CSNB in mind should be actively considered.

Q Can complete and incomplete types be distinguished by symptoms?

A

Differentiation by symptoms alone can be difficult. The complete type tends to present with the triad of night blindness, nystagmus, and high myopia, whereas the incomplete type often does not complain of night blindness and frequently presents only with decreased vision. For definitive differentiation, detailed ERG testing (measuring rod and cone responses separately) is essential.

3. Causes and Risk Factors

Inheritance Patterns and Main Causative Genes

CSNB is a group of monogenic diseases with several known inheritance patterns. X-linked recessive inheritance is the most common, affecting males predominantly, but autosomal recessive and autosomal dominant forms have also been reported.

Gene	Inheritance Pattern	Disease Type	Functional Pathway
NYX	X-linked recessive	cCSNB	Nyctalopin (LRR protein). Involved in stabilization of TRPM1. “Nyx” derives from the Greek goddess of night 1)
CACNA1F	X-linked recessive	iCSNB	Voltage-gated L-type calcium channel alpha1F subunit. Controls neurotransmitter release at photoreceptor synaptic terminals 1)
GRM6	Autosomal recessive	cCSNB	Metabotropic glutamate receptor (mGluR6). Synaptic transmission of ON bipolar cells1)
TRPM1	Autosomal recessive	cCSNB	Cation channel at the tip of ON bipolar cell dendrites. Responsible for depolarization upon light stimulation1)
GPR179	Autosomal recessive	cCSNB	Orphan GPCR. Regulatory scaffold of the mGluR6/TRPM1 signaling cascade1)
LRIT3	Autosomal recessive	cCSNB	LRR protein required for ON bipolar cell function1)
GNAT1	Autosomal dominant	Riggs type	Rod transducin alpha subunit
SLC24A1	Autosomal recessive	Riggs type	Na/K/Ca ion exchanger (involved in dark current recovery of rods)
CABP4	Autosomal recessive	iCSNB	Cav1.4 regulatory protein. Called “congenital cone-rod synaptic disorder”3)
CACNA2D4	Autosomal recessive	iCSNB	Voltage-gated calcium channel auxiliary subunit
RDH5	Autosomal recessive	White dot fundus	Visual cycle enzyme in RPE
GRK1	Autosomal recessive	Oguchi disease	Rhodopsin kinase
SAG	Autosomal recessive	Oguchi disease	Arrestin (binds phosphorylated rhodopsin)

The inheritance pattern for both complete and incomplete types is mostly X-linked recessive, but the causative gene for the complete type is NYX, and for the incomplete type is CACNA1F. In recent years, autosomal recessive inheritance has also been reported for both types.

Risk Factors

Since X-linked recessive inheritance is the most common, the mother of an affected individual is almost always a carrier. In autosomal recessive cases, siblings have a 25% risk of being affected. If the causative mutation is identified through genetic testing, carrier diagnosis and prenatal diagnosis are possible.

About Genetic Counseling

Since CSNB is often X-linked recessive, genetic counseling is recommended once the diagnosis is confirmed. It allows for identification of carriers (often the mother), assessment of risk for siblings, and consultation regarding future pregnancies. Please discuss with your primary care physician about a referral to a genetic specialist or genetic counselor.

4. Diagnosis and Testing Methods

ERG Diagnosis (Most Important Test)

ERG plays a decisive role in the diagnosis of CSNB. In children with poor vision or nystagmus but a normal fundus, ERG testing is essential.

Standard Flash ERG

Both complete and incomplete types show a negative-type ERG in response to flash stimulation under dark adaptation. A negative-type ERG is a waveform pattern in which the a-wave is relatively preserved, but the b-wave is markedly reduced or absent, which is characteristic of the Schubert-Bornschein type.

Detailed ERG (Differentiation Between Complete and Incomplete Types)

Since standard flash ERG cannot differentiate between complete and incomplete types, a detailed ERG test that separates rod and cone responses is necessary.

ERG findings	Complete type (cCSNB)	Incomplete type (iCSNB)
Dark-adapted rod response (DA 0.01)	Absent	Residual (reduced)
Dark-adapted mixed response (DA 3.0)	Negative type (b-wave absent)	Negative type (b-wave reduced)
Light-adapted cone response (LA 3.0)	Preserved	Reduced
30Hz flicker	Normal to mildly reduced	Reduced

In the complete type, the b-wave in DA 0.01 is absent, reflecting complete functional loss of ON bipolar cells ¹⁾. In the incomplete type, both rod and cone responses are reduced but not absent. A small cone response is characteristic of the incomplete type.

ERG Classification Summary

Classification	ERG Pattern	Affected Site
Schubert-Bornschein complete type	Dark-adapted negative type, rod response absent, cone response preserved	ON-type bipolar cells
Schubert-Bornschein incomplete type	Dark-adapted negative type, both rod and cone responses reduced	ON/OFF-type bipolar cells
Riggs type	Abnormality of the a-wave itself	Rod photoreceptors

OCT (Optical Coherence Tomography)

SD-OCT shows INL thinning in some complete-type cases¹⁾. It is recommended as a standard ancillary diagnostic test.

Genetic Testing

Next-generation sequencing (NGS) enables definitive diagnosis, and standard gene panel testing can identify genetic diagnoses in 70–80% of cases⁸⁾. Reports from a Taiwanese cohort indicate that, in addition to novel CACNA1F mutations, mutations in other inherited retinal disease-related genes such as RHO, SLC24A1, GNAT1, CABP4, CACNA2D4, GRK1, RDH5, RLBP1, RPE65, SAG, and PDE6B may present with CSNB-like phenotypes¹⁾. Whole-genome sequencing (WGS) shows superior detection ability for structural variants that are difficult to detect by standard exome sequencing⁸⁾. In children, portable ERG (RETeval) is also useful as a diagnostic aid⁷⁾.

Differential Diagnosis

• Amblyopia: Normal fundus and normal ERG. ERG is the definitive differentiating point from CSNB.
• Retinitis pigmentosa (RP): Progressive, with bone-spicule pigmentation in the fundus.
• Leber congenital amaurosis (LCA): More severe visual impairment, markedly reduced to absent ERG.
• Achromatopsia: Abnormal photopic ERG.
• Oguchi disease and fundus albipunctatus: These fall under stationary night blindness but can be differentiated by characteristic fundus findings.

Differentiation from amblyopia

The key to differentiating CSNB is that the fundus is normal but the ERG is abnormal. In amblyopia, the fundus is normal and the ERG is also normal (or improves over time), whereas in CSNB, the ERG shows persistent abnormalities. ERG testing should be considered for visual impairment that does not respond to amblyopia treatment (occlusion therapy).

5. Standard treatment

Basic Treatment Policy

There is currently no fundamental treatment for CSNB. The main focus of treatment is symptom management and prevention of complications.

Refractive Correction

Complete-type CSNB is often accompanied by high myopia, so appropriate prescription of glasses or contact lenses is important. If amblyopia is also present, amblyopia treatment should be performed concurrently, but it should be noted that the effect of amblyopia treatment may be limited in CSNB ⁷⁾. To maximize the potential for visual improvement, early correction is recommended. Tinted lenses are useful for photophobia.

Regular Follow-up

Regular ERG and visual acuity follow-up should be performed to confirm that the condition is non-progressive. In adulthood, attention must be paid to the complication of glaucoma. Particularly in the complete type with high myopia, intraocular pressure management is important.

Lifestyle Guidance

• Provide appropriate warnings regarding activities in dark places (e.g., night walking, night driving).
• For driver’s licenses, individual responses may be necessary depending on the degree of night blindness.
• Guidance on considering the light environment should be provided for sports activities and career choices.

Genetic Counseling

Since X-linked recessive inheritance is the most common, confirmation of carrier status (mother) is important. In autosomal recessive cases, siblings have a 25% risk of being affected. If the causative mutation is identified, carrier diagnosis and prenatal diagnosis become possible. Comprehensive genetic counseling including psychological support is recommended.

Q Where can I receive genetic counseling?

A

Genetic counseling is available at university hospitals and specialized medical institutions in departments of genetics, pediatrics, or ophthalmology. Clinical geneticists and certified genetic counselors provide consultations. Since CSNB is often X-linked recessive and there is a high likelihood of carriers within the family, early consultation after diagnosis is recommended.

6. Pathophysiology and Detailed Mechanisms of Onset

Normal Phototransduction

When a rod cell receives light, glutamate release decreases. In ON bipolar cells, mGluR6 (metabotropic glutamate receptor type 6) senses this change, releasing the activation of Gαoβ3γ13, which opens the TRPM1 channel and depolarizes the cell. This cascade underlies the processing of light signals in the retina. The TRPM1 channel fully opens approximately 100 milliseconds after mGluR6 activation, which is five times faster than the opening of the cGMP-dependent channel in rods¹⁾.

Abnormalities in complete congenital stationary night blindness (cCSNB)

The pathology of complete CSNB is due to functional loss of ON bipolar cells. TRPM1, mGluR6, and nyctalopin (NYX) form a tri-molecular complex that is essential for ON bipolar cell function¹⁾. Disruption of this complex prevents ON bipolar cells from depolarizing, resulting in the loss of the b-wave on ERG. Since OFF bipolar cell function is preserved, cone-mediated ERG responses remain.

• NYX mutation: Nyctalopin is involved in the transport and stabilization of TRPM1 to the cell surface.
• GRM6 mutation: Light response signal is not transmitted to Gαo due to loss of mGluR6 function
• TRPM1 mutation: Loss of channel function itself
• GPR179 mutation: Loss of scaffold protein function in the mGluR6/TRPM1 signaling cascade
• LRIT3 mutation: Deficiency of a protein required for maintaining ON bipolar cell function

Abnormalities in Incomplete Type (iCSNB)

The pathology of the incomplete type involves dysfunction of both ON-type and OFF-type bipolar cells. Abnormalities in the main causative gene CACNA1F (voltage-gated L-type calcium channel alpha1F subunit) impair Ca²⁺ influx at the photoreceptor synaptic terminal. Consequently, neurotransmitter release becomes abnormal, reducing the function of both ON and OFF bipolar cells. This is understood as synaptic dysfunction between photoreceptors and bipolar cells.

Abnormalities in Riggs Type

The Riggs type is caused by abnormal phototransduction within the rod photoreceptors themselves. Mutations in GNAT1 (rod transducin alpha subunit) or SLC24A1 (Na/K/Ca exchanger) impair phototransduction at the photoreceptor level. In ERG, abnormalities in the a-wave itself are observed, showing a pattern distinct from the Schubert-Bornschein type.

Association with high myopia

In NYX knockout mice, a predisposition to myopia and decreased dopamine levels have been observed, providing clues to the pathogenesis of high myopia associated with CSNB ¹⁾. It is being studied whether the intraocular dopamine system is involved in axial length regulation in conjunction with ON bipolar cell activity.

Prognosis

In most cases, the condition is non-progressive, and visual acuity and ERG do not change over time. Rarely, cases of progressive retinal and optic nerve atrophy have been reported in individuals with CACNA1F gene mutations. After adulthood, continued attention to comorbid conditions such as glaucoma is necessary.

7. Latest Research and Future Prospects

For Patients: Please Read

The following information is currently at the research stage and is not a standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Gene Replacement Therapy (Animal Models)

Currently, there is no approved gene therapy for CSNB. However, research is actively progressing in animal models¹⁾.

NYX-associated cCSNB model (Nyxnob mouse):

Intravitreal injection of AAV2(quadY-F+TV)-Ple155-YFP_Nyx at P2 (postnatal day 2) resulted in recovery of the b-wave and restoration of TRPM1 localization. No effect was observed at P30, suggesting that early developmental intervention is important¹⁾.

LRIT3-associated cCSNB model (Lrit3−/− mouse):

Administration of rAAV RHO::Lrit3 at P5 achieved restoration of TRPM1 localization and 50% recovery of the DA b-wave. Effects were also confirmed in P35 (adult) mice, suggesting potential applicability to adult-onset cases. Administration of AAV2-7m8 at P30 achieved 58% recovery of the DA b-wave, with effects persisting after 4 months¹⁾.

GRM6-associated cCSNB model (Grm6−/− mice):

Although AAV2-7m8 administration restored mGluR6 expression, ERG recovery was not achieved. This is presumed to be due to structural abnormalities during development, suggesting the importance of early intervention in this genotype¹⁾.

Canine model (CSNB beagle dogs):

Administration of AAV K9#12-shGRM6-cLRIT3-WPRE resulted in stable recovery of the ERG b-wave to 30% of wild-type levels, with effects persisting for over 1.2 years¹⁾.

Challenges in Gene Editing Technology and AAV Vectors

CRISPR/Cas9, base editing, and prime editing have not yet been reported for clinical application in CSNB, but for CEP290-mutant LCA10, retinal SaCas9 has advanced to Phase 1/2 clinical trials¹⁾. AAV7m8 did not show the expected efficacy in primates, highlighting species differences as a challenge. Development of non-viral vectors such as lipid nanoparticles (LNPs) and virus-like particles (VLPs) is also ongoing¹⁾.

Diagnostic Advantages of Whole-Genome Sequencing

It has been shown that WGS can identify structural variants that are difficult to detect with standard exome analysis ⁸⁾.

Martinez Sanchez et al. (2025) diagnosed a CSNB case that was difficult to diagnose with standard sequencing using WGS, and identified a novel structural variant in the CACNA1F gene ⁸⁾.

Transcriptome analysis

RNA-seq (whole transcriptome analysis) is being applied to search for unidentified CSNB-related genes, and it is expected to identify novel causative genes ¹⁾.

Expansion of Genetic Panel Testing

With the recent spread of genetic panel testing (NGS), the accuracy of differentiating CSNB from other diseases that present similar phenotypes (such as inherited retinal diseases caused by mutations in RPE65, SAG, PDE6B, etc.) is improving ¹⁾.

8. References

1. Mordà D, Alibrandi S, Scimone C, et al. Decoding pediatric inherited retinal dystrophies: Bridging genetic complexity and clinical heterogeneity. Prog Retin Eye Res. 2025;109:101405.
2. Zhang Y, Lin S, Yu L, et al. Gene therapy shines light on congenital stationary night blindness for future cures. J Transl Med. 2025;23:392.
3. Tan JK, Arno G, Josifova D, et al. Unusual OCT findings in a patient with CABP4-associated cone-rod synaptic disorder. Doc Ophthalmol. 2024;148:115-120.
4. Koschak A, Fernandez-Quintero ML, Heigl T, et al. Cav1.4 dysfunction and congenital stationary night blindness type 2. Pflugers Arch. 2021;473:1437-1454.
5. Cammarata G, Mihalich A, Manfredini E, et al. Optic neuropathy AFG3L2 related in a patient affected by congenital stationary night blindness. Case Rep Ophthalmol Med. 2024;2024:8581090.
6. Hauser BM, Place E, Huckfeldt R, et al. A novel homozygous nonsense variant in CABP4 causing stationary cone/rod synaptic dysfunction. Ophthalmic Genet. 2024;45(6):640-645.
7. Wen L, Liu Y, Yang Z, et al. Novel CACNA1F pathogenic variant in pediatric incomplete X-linked CSNB: integrating portable ERG and genetic analysis. Doc Ophthalmol. 2025;150:33-39.
8. Martinez Sanchez M, Meher N, DeBruyn H, et al. Novel structural variant in CACNA1F causing congenital stationary night blindness identified with whole genome sequencing. Ophthalmic Genet. 2025;46(6):692-696.
9. Mahmood U, Mejecase C, Ali SMA, et al. A novel splice-site variant in CACNA1F causes a phenotype synonymous with Aland Island eye disease and incomplete congenital stationary night blindness. Genes. 2021;12:171.