Congenital Stationary Night Blindness (CSNB)

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Disease Entity

Congenital Stationary Night Blindness (CSNB) is recognized by the following codes as per the International Classification of Diseases (ICD) nomenclature.

ICD-10

H53.63 Congenital Stationary Night Blindness (CSNB)

Pathophysiology

CSNB is the term for a collection of rare genetic diseases affecting photoreceptors, the retinal pigment epithelium (RPE), or bipolar cells. Generally, affected individuals exhibit dark or dim-light visual difficulties or delayed dark adaptation. Current research has implicated numerous genetic mutations primarily affecting 17 different genes to cause CSNB (Table 1). These mutations span different modes of inheritance, including x-linked, autosomal dominant (AD), and autosomal recessive (AR).

Table 1. Genetic mutations underlying CSNB. AD = autosomal dominant; AR = autosomal recessive; X = x-linked
Mutation Inheritance Encoded Protein Function Electroretinogram (ERG) Findings
Cabp4 AR Calcium binding protein within bipolar cells
  • Normal scotopic bright flash a-wave
  • Attenuated scotopic bright flash b-wave
  • Subnormalscotopic dim flash b-wave
Cacna1f X Subunit of a calcium voltage-gated channel within bipolar cells
  • Normal scotopic bright flash a-wave
  • Attenuated scotopic bright flash b-wave
  • Subnormal scotopic dim flash b-wave
Cacna2d4 AR Subunit of a calcium voltage-gated channel within bipolar cells
  • Normal scotopic bright flash a-wave
  • Attenuated scotopic bright flash b-wave
  • Subnormal scotopic dim flash b-wave
Gnat1 AD Subunit of transducin involved in rod phototransduction
  • Attenuated scotopic bright flash a-wave
  • Normal photopic response
Gpr179 AR Glutamate receptor on surface of bipolar cells involved in signal transmission from rods
  • Normal scotopic bright flash a-wave
  • Attenuated scotopic bright flash b-wave
  • No detectable scotopic dim flash b-wave
Grk1 AR G-protein coupled receptor kinase within rods responsible for phosphorylating activated rhodopsin to deactivate the phototransduction cascade
  • Attenuated scotopic bright flash a-wave
  • Prolonged dark adaptation shows recovery of scotopic bright flash a- and b-waves for one flash, then subsequent flash exhibits attenuated waveforms
  • Normal photopic response
Grm6 AR Glutamate receptor on surface of bipolar cells involved in signal transmission from rods
  • Normal scotopic bright flash a-wave
  • Attenuated scotopic bright flash b-wave
  • No detectable scotopic dim flash b-wave
Lrit3 AR Regulatory protein required for proper localization of ion channels encoded by Trpm1 in bipolar cells
  • Normal scotopic bright flash a-wave
  • Attenuated scotopic bright flash b-wave
  • No detectable scotopic dim flash b-wave
Nyx X Nyctalopin protein (function unknown) within bipolar cells involved in signal transmission from rods
  • Normal scotopic bright flash a-wave
  • Attenuated scotopic bright flash b-wave
  • No detectable scotopic dim flash b-wave
Pde6b AD Subunit of phosphodiesterase protein involved in rod phototransduction
  • Attenuated scotopic bright flash a-wave
  • Normal photopic response
Rdh5 AR Retinol dehydrogenase converts 11-cis retinol to 11-cis retinal within the RPE to promote visual cycle function
  • Attenuated scotopic bright flash a-wave
  • Prolonged dark adaptation shows recovery of scotopic bright flash a-wave
  • Normal photopic response
Rho AD G-protein coupled receptor involved in rod phototransduction
  • Attenuated scotopic bright flash a-wave
  • Normal photopic response
Rlbp1 AR Binding protein for stabilizing 11-cis retinal and 11-cis retinol within the RPE to promote visual cycle function    
  • Attenuated scotopic bright flash a-wave
  • Prolonged dark adaptation shows recovery of scotopic bright flash a-wave
  • Normal photopic response    
Rpe65 AR Involved in utilizing 11-cis retinol within the RPE and cones to promote visual cycle function (exact function unknown)    
  • Attenuated scotopic bright flash a-wave
  • Attenuated photopic response
Sag AR Arrestin protein involved in desensitizing the phototransduction cascade within rods
  • Attenuated scotopic bright flash a-wave
  • Prolonged dark adaptation shows recovery of scotopic bright flash a- and b-waves for one flash, then subsequent flash exhibits attenuated waveforms
  • Normal photopic response    
Slc24a1 AR Subunit of a potassium-dependent sodium/calcium channel exchanger involved in rod phototransduction
  • Attenuated scotopic a-wave
  • Normal photopic response    
Trpm1 AR Ion channel within bipolar cells involved in signal transmission from rods
  • Normal scotopic bright flash a-wave
  • Attenuated scotopic bright flash b-wave
  • No detectable scotopic dim flash b-wave

General Pathology

Figure 1. Localization of products of gene mutations known to cause CSNB. RPE = retinal pigment epithelium.

CSNB is a retinal disease that primary affects signaling processing within photoreceptors, retinoid recycling in the RPE, and signal transmission via bipolar cells (Figure 1). Seventeen genes with more than 360 mutations and 670 alleles have been found to be associated with CSNB (Figure 2).

CSNB can be classified as complete (cCSNB) and incomplete (iCSNB). cCSNB is characterized by a defect that localizes to the ON bipolar cells, leading to an alteration of signaling to the bipolar cells. The ERG in cCSNB shows no rod response. In iCSNB, the defect is localized to the photoreceptor synapse, leading to altered signaling to both ON and OFF bipolar cells. The ERG in iCSNB shows a diminished but recordable rod response. 

Primary prevention

There is currently no preventative measures for this disease.

Diagnosis

History

A detailed family history for night blindness and/or decreased vision should be elicited.

Physical examination

Figure 2. Schematic of proteins involved in phototransduction that can cause CSNB. Proteins whose dysfunction can cause CSNB are marked in red. RPE = retinal pigment epithelium; cGMP = cyclic guanosine monophosphate

Patients should undergo a full ophthalmic examination, including a dilated fundus exam to evaluate for congenital night blindness with fundus abnormalities.

Signs & Symptoms

Patients with CSNB may complain of poor night or dim-light vision. These symptoms are often subjective and may not be appreciated by those who live in well-lit urban areas. Patients can also present with myopia, strabismus, and nystagmus. Eye-movement recordings in CSNB patients reveal a predominantly disconjugate pendular nystagmus of small amplitude, high frequency, and oblique direction.

Clinical diagnosis

Most CSNB patients have a normal fundus exam; however, a small subset has abnormal fundus findings (Figure 3). CNSB without fundus abnormalities can be subdivided into two categories based on ERG findings: 1) Riggs and 2) Schubert-Bornstein (Figure 4). For a more detailed description of electroretinography (ERG), please refer to following article (ERG).

The Riggs subtype is associated with photoreceptor dysfunction, with a scotopic ERG characterized by a decreased a-wave amplitude and an electronegative waveform. Photopic ERG remains normal, indicating preserved cone function.

The Schubert-Bornstein subtype is associated with bipolar cell dysfunction. The ERG reflects dysfunction in signaling between photoreceptors and bipolar cells. The most common pattern observed is a negative scotopic ERG, characterized by a normal a-wave but a reduced b-wave.

Figure 3. Categories of CSNB

This subtype can further be divided into complete and incomplete forms. The complete form is associated with ON bipolar pathway dysfunction. Scotopic ERG shows no detectable signal with dim flash and a negative ERG with bright flash. Photopic ERG often exhibits a normal a-wave but with a broadened trough and a sharply increasing b-wave with loss of oscillatory potentials.  A long response stimulus can be used to confirm the diagnosis: the ON pathway shows the characteristic negative ERG while the OFF pathway is normal. The incomplete form of CSNB is associated with ON and OFF pathway dysfunction. The scotopic dim-flash ERG signal is present, but the amplitude of the a-wave is diminished, while the bright-flash ERG shows an electronegative waveform. The photopic response is more severely affected compared to the complete form: the flicker ERG signal is delayed and often displays a bifid peak.

Fundus albipunctatus and Oguchi disease are two entities within CSNB that are associated with fundus findings. Patients with fundus albipunctatus demonstrate scattered yellow-white dots in the posterior pole that extend to the mid-periphery. These dots have been presumed to contain 11-cis retinal precursors and exist from the RPE/Bruch membrane complex to the inner limiting membrane . Those with Oguchi disease demonstrate the Mizuo-Nakamura phenomenon; the fundus is unremarkable in the dark-adapted state but has a yellow iridescent sheen after light exposure. The mechanism underlying this process is currently not well understood.

Diagnostic procedures

Figure 4. Scotopic ERG waveforms of CSNB.

ERG plays an important role in the diagnosis of CSNB. The most common ERG pattern is the Schubert-Bornschein negative ERG, in which the bright flash scotopic ERG has a normal a-wave but a reduced b-wave. Dark adaptation is abnormal in all patients with CSNB. Newborns might have a negative ERG until 6 months of age. After that, the ERG usually converts to the classic negative form.

Laboratory test

Genetic testing for known mutations might be offered to patients.

Differential diagnosis

Retinitis pigmentosa, Rod-cone dystrophy

Management

There are currently no treatments for CSNB.   Photoreceptor replacement by transplantation and gene therapy are modalities under investigation. 

Prognosis

Generally, the clinical course of patients with CSNB does not change over time. The longest follow up documented in the literature is a patient who was followed for 38 years. Further accumulation of clinical date is needed to establish prognostic factors for CSNB.

Additional Resources

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References

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