abnormal ERG

Cranial Dysinnervation Disorders with Strabismus and Arthrogryposis

Clinical Characteristics

Ocular Features:

Strabismus and/or ophthalmoplegia are important features of a group of conditions known as cranial dysinnervation disorders. Ptosis, Duane syndrome, V pattern exotropia and various degrees of ophthalmoplegia may be seen. There may be considerable asymmetry in the manifestations in the two eyes. Epicanthal folds, blepharophimosis, and hypermetropia are sometimes present. Some patients have corneal leukomas, keratoglobus, high corneal astigmatism, and dysplastic optic disks.

A pigmentary retinopathy and folds in the macula with an abnormal ERG has been reported. Subnormal vision has been reported in some patients.

Systemic Features:

Patients are often short in stature with pectus excavatum, spine stiffness, highly arched palate, and club feet. Limited forearm rotation and wrist extension may be present. The fingers appear long and often have contractures while the palmar and phalangeal creases may be absent. Camptodactyly and clinodactyly are common. Deep tendon reflexes are often hyporeactive and decreased muscle mass has been noted. The muscles seem "firm" to palpation. Restrictive lung disease has been reported. Hearing loss is experienced by some individuals.

Genetics

Distal arthrogryposis type 5D is caused by homozygous or compound heterozygous mutations in the ECEL1 gene located at 2q36. However, a similar phenotype (albeit with more severe ocular manifestations) results from heterozygous mutations in PIEZO2 (18p11). Heterozygous mutations in the PIEZO2 gene have also been reported to cause distal arthrogryposis type 3 (Gordon syndrome [114300]) and Marden-Walker syndrome (248700) and all of these may be simply phenotypical variations of the same disorder.

Pedigree:

Autosomal dominant

Autosomal recessive

Treatment

Treatment Options:

There is no treatment for this condition. Patients with subnormal vision may benefit from low vision aids and selective surgery may be helpful in reducing the physical restrictions from physical deformities.

References

Article Title:

The ECEL1-related strabismus phenotype is consistent with congenital cranial dysinnervation disorder

Khan AO, Shaheen R, Alkuraya FS. The ECEL1-related strabismus phenotype is consistent with congenital cranial dysinnervation disorder. J AAPOS. 2014 Aug;18(4):362-7.

PubMed ID:

25173900

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5

McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM Jr, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014 May 1;94(5):734-44.

PubMed ID:

24726473

Distal arthrogryposis 5: a dominant syndrome of peripheral contractures and ophthalmoplegia

Beals RK, Weleber RG. Distal arthrogryposis 5: a dominant syndrome of peripheral contractures and ophthalmoplegia. Am J Med Genet A. 2004 Nov 15;131(1):67-70. PubMed PMID: 15389706.

PubMed ID:

15389706

Distal arthrogryposis type IIB: unreported ophthalmic findings

Sahni J, Kaye SB, Fryer A, Hiscott P, Bucknall RC. Distal arthrogryposis type IIB: unreported ophthalmic findings. Am J Med Genet A. 2004 May 15;127A(1):35-9.

PubMed ID:

15103714

Arthrogryposis, ophthalmoplegia, and retinopathy: confirmation of a new type of arthrogryposis

Arthrogryposis, ophthalmoplegia, and retinopathy: confirmation of a new type of arthrogryposis. C T Schrander-Stumpel, C J Howeler, A D Reekers, N M De Smet, J G Hall, J P Fryns J Med Genet. 1993 January; 30(1): 78–80.

PubMed ID:

8423615

Night Blindness, Congenital Stationary, CSNB1E

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. The photopic ERG is usually abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

The onset of night blindness in type 1E occurs in early childhood and may be congenital. Some degree of nystagmus is usually present. It is usually only slowly progressive.

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

This type of congenital stationary night blindness is inherited in an autosomal recessive pattern resulting from homozygous or compound heterozygous mutations in GPR179. The gene encodes an orphan G protein receptor.

Other autosomal recessive CSNB disorders are: CSNB2B (610427), CSNB1B (257270), and CSNB1C (613216).

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Article Title:

Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness

Audo I, Bujakowska K, Orhan E, Poloschek CM, Defoort-Dhellemmes S, Drumare I, Kohl S, Luu TD, Lecompte O, Zrenner E, Lancelot ME, Antonio A, Germain A, Michiels C, Audier C, Letexier M, Saraiva JP, Leroy BP, Munier FL, Mohand-Sa?Od S, Lorenz B, Friedburg C, Preising M, Kellner U, Renner AB, Moskova-Doumanova V, Berger W, Wissinger B, Hamel CP, Schorderet DF, De Baere E, Sharon D, Banin E, Jacobson SG, Bonneau D, Zanlonghi X, Le Meur G, Casteels I, Koenekoop R, Long VW, Meire F, Prescott K, de Ravel T, Simmons I, Nguyen H, Dollfus H, Poch O, L?(c)veillard T, Nguyen-Ba-Charvet K, Sahel JA, Bhattacharya SS, Zeitz C. Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness. Am J Hum Genet. 2012 Feb 10;90(2):321-30.

PubMed ID:

22325361

GPR179 Is Required for Depolarizing Bipolar Cell Function and Is Mutated in Autosomal-Recessive Complete Congenital Stationary Night Blindness

Peachey NS, Ray TA, Florijn R, Rowe LB, Sjoerdsma T, Contreras-Alcantara S, Baba K, Tosini G, Pozdeyev N, Iuvone PM, Bojang P Jr, Pearring JN, Simonsz HJ, van Genderen M, Birch DG, Traboulsi EI, Dorfman A, Lopez I, Ren H, Goldberg AF, Nishina PM, Lachapelle P, McCall MA, Koenekoop RK, Bergen AA, Kamermans M, Gregg RG. GPR179 Is Required for Depolarizing Bipolar Cell Function and Is Mutated in Autosomal-Recessive Complete Congenital Stationary Night Blindness. Am J Hum Genet. 2012 Feb 10;90(2):331-9.

PubMed ID:

22325362

Night Blindness, Congenital Stationary, CSNBAD3

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. However, the photopic ERG can be abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision. Nystagmus and photophobia are usually not features. Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies. The amount of pigmentary retinopathy is highly variable.

This disorder (CSNBAD3), one of three autosomal dominant CSNB conditions, is known primarily from a single large family in Southern France. All affected individuals descended from Jean Nougaret from which the eponym is derived. The published pedigree by F. Cunier in 1838 is probably the first illustrating autosomal dominant inheritance of a human disease. Rod a-waves are completely absent suggesting complete lack of rod function. Night vision in dim conditions was reduced but not with bright backgrounds. Daytime vision is normal as is color vision. Rare patients have peripheral pigmentary changes with visual field restriction.

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

CSNBAD3, or type AD3, is one of three congenital nightblindness disorders with autosomal dominant inheritance. It results from mutations in the GNAT1 gene (3p21) gene encoding a subunit of rod transducin which couples rhodopsin as part of the phototransduction cascade.

A consanguineous Pakistani family with 4 affected children in a pedigree suggestive of autosomal recessive inheritance has been reported (CSNB1G). All individuals with congenital nightblindness were homozygous for a missense mutation in GNAT1 while unaffected persons were heterozygous (616389).

Other autosomal dominant CSNB disorders are: CSNBAD2 (163500) and CSNBAD1 (610445). Three CSNB disorders are transmitted in an autosomal recessive pattern and two as X-linked recessives.

Pedigree:

Autosomal dominant

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Article Title:

GNAT1 associated with Autosomal Recessive Congenital Stationary Night Blindness

Naeem MA, Chavali VR, Ali S, Iqbal M, Riazuddin S, Khan SN, Husnain T, Sieving PA, Ayyagari R, Riazuddin S, Hejtmancik JF, Riazuddin SA. GNAT1 associated with Autosomal Recessive Congenital Stationary Night Blindness. Invest Ophthalmol Vis Sci. 2011 Dec 21. [Epub ahead of print]

PubMed ID:

22190596

The molecular basis of human retinal and vitreoretinal diseases

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75.

PubMed ID:

20362068

Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of congenital stationary night blindness

Dryja TP, Hahn LB, Reboul T, Arnaud B. Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of congenital stationary night blindness. Nat Genet. 1996 Jul;13(3):358-60.

PubMed ID:

8673138

Night Blindness, Congenital Stationary, CSNBAD2

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. However, the photopic ERG can be abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision. Nystagmus and photophobia are usually not features. Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies. The amount of pigmentary retinopathy is highly variable.

This disorder (CSNBAD2) is one of three autosomal dominant CSNB conditions. ERG responses were identical to those found in the Nougaret type of autosomal dominant CSNB. Rod a-wave responses to single flashes are completely absent suggesting complete lack of rod function. The residual b-wave suggests some cone response. Daytime and color vision are normal.

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

CSNBAD2, or type AD2, is one of three congenital nightblindness disorders with autosomal dominant inheritance. It results from mutations in the PDE6B gene (4p16.3) encoding a subunit of rod cGMP-specific phosphodiesterase.

Other CSNB disorders inherited in an autosomal dominant pattern are CSNBAD1 (610445) and CSNBAD3 (610444).

Three CSNB disorders are transmitted in an autosomal recessive pattern and two as X-linked recessives.

Pedigree:

Autosomal dominant

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Article Title:

The molecular basis of human retinal and vitreoretinal diseases

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75.

PubMed ID:

20362068

Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness

Gal A, Orth U, Baehr W, Schwinger E, Rosenberg T. Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness. Nat Genet. 1994 May;7(1):64-8. Erratum in: Nat Genet. 1994 Aug;7(4):551.

PubMed ID:

8075643

Night Blindness, Congenital Stationary, CSNBAD1

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. The photopic ERG is usually abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision. Nystagmus and photophobia are usually not features. Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies. The amount of pigmentary retinopathy is highly variable.

In this disorder (CSNBAD1), one of three autosomal dominant CSNB conditions, the b-wave responses are absent (no scotopic response) with some a-wave decrease in amplitude under dark adapted conditions. Night vision in dim conditions may be reduced but not with bright backgrounds. Daytime vision is normal as is color vision. Older patients can have peripheral bone-spicule pigmentary changes with visual field restriction and narrowing of retinal arterioles.

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

CSNBAD1, or type AD1, is one of three congenital nightblindness disorders with autosomal dominant inheritance. It results from mutations in the RHO (3q21-q24) gene coding rhodopsin.

Other autosomal dominant CSNB disorders are: CSNBAD2 (163500) and CSNBAD3 (610444). Three CSNB disorders are transmitted in an autosomal recessive pattern and 2 as X-linked recessives.

Pedigree:

Autosomal dominant

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Article Title:

The molecular basis of human retinal and vitreoretinal diseases

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75.

PubMed ID:

20362068

A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness

al-Jandal N, Farrar GJ, Kiang AS, Humphries MM, Bannon N, Findlay JB, Humphries P, Kenna PF. A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness. Hum Mutat. 1999;13(1):75-81.

PubMed ID:

9888392

Dark-light: model for nightblindness from the human rhodopsin Gly-90-->Asp mutation

Sieving PA, Richards JE, Naarendorp F, Bingham EL, Scott K, Alpern M. Dark-light: model for nightblindness from the human rhodopsin Gly-90-->Asp mutation. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):880-4.

PubMed ID:

7846071

Night Blindness, Congenital Stationary, CSNB2B

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. The photopic ERG is usually abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

In this disorder (CSNB2B) the b-wave responses are deficient (little or no scotopic response) and a-waves seem to be normal. However, many if not most patients do not complain of night blindness. Nystagmus, strabismus, and restriction of visual fields may be present. Visual acuity is mildly to severely reduced.

Foveal thinning has been documented in this condition.

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

CSNB2B, or type 2B, is one of four congenital nightblindness disorders with autosomal recessive inheritance. It results from mutations in the CAPB4 gene (11q13.1) important in receptor to bipolar cell signaling.

Other autosomal recessive CSNB disorders are: CSNB1C (613216), CSNB (unclassified; OMIM number pending), and CSNB1B (257270).

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Article Title:

Multimodal imaging in CABP4-related retinopathy

Schatz P, Elsayed MEAA, Khan AO. Multimodal imaging in CABP4-related retinopathy. Ophthalmic Genet. 2017 Mar 1:1-6. doi: 10.1080/13816810.2017.1289543.

PubMed ID:

28635425

Clinical characterisation of the CABP4-related retinal phenotype

Khan AO, Alrashed M, Alkuraya FS. Clinical characterisation of the CABP4-related retinal phenotype. Br J Ophthalmol. 2012 Oct 25. [Epub ahead of print].

PubMed ID:

23099293

The molecular basis of human retinal and vitreoretinal diseases

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75.

PubMed ID:

20362068

Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness

Zeitz C, Kloeckener-Gruissem B, Forster U, Kohl S, Magyar I, Wissinger B, M?degty?degs G, Borruat FX, Schorderet DF, Zrenner E, Munier FL, Berger W. Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness. Am J Hum Genet. 2006 Oct;79(4):657-67.

PubMed ID:

16960802

Night Blindness, Congenital Stationary, CSNB2A

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. However, the photopic ERG can be abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision. Nystagmus and photophobia are usually not features. Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies. The amount of pigmentary retinopathy is highly variable.

CSNB2A, or type 2A, is associated with myopia which ranges from mild to severe. Residual rod function is diminished but not completely absent as suggested by the presence of small b-waves. Cone function is impacted to some degree as well. Nystagmus and strabismus are inconsistent findings. Retinal pigmentation is usually normal in the X-linked forms. Visual acuity ranges from 20/30 to 20/200. Night blindness is less severe in this form than in another X-linked CSNB (CSNB1A; 310500). Mild dyschromatopsia is present in some patients but this is primarily a disease of rods.

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

Congenital stationary night blindness type 2A is an X-linked disorder caused by a mutation in the CACNA1F gene located at Xp11.23. Only males are affected and carrier females do not have clinical disease.

This disorder is allelic to Aland Island Eye Disease (300600) from which it differs by an apparent lack of progressive myopia and the presence of a normal fovea. Aland Island Eye Disease has foveal hypoplasia as well as iris and fundus hypopigmentation.

Another allelic disorder with mutations in CACNA1F is CORDX3 (300476), a cone-rod dystrophy.

Approximately 55% of X-linked CSNB are of this type while about 45% have another X-linked form known as CSNB1A, or type 1A (310500) secondary to a mutation at Xp11.4.

Pedigree:

X-linked recessive, carrier mother

X-linked recessive, father affected

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Article Title:

The molecular basis of human retinal and vitreoretinal diseases

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75.

PubMed ID:

20362068

Evidence for genetic heterogeneity in X-linked congenital stationary night blindness

Boycott KM, Pearce WG, Musarella MA, Weleber RG, Maybaum TA, Birch DG, Miyake Y, Young RS, Bech-Hansen NT. Evidence for genetic heterogeneity in X-linked congenital stationary night blindness. Am J Hum Genet. 1998 Apr;62(4):865-75.

PubMed ID:

9529339

An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness

Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K, Gutwillinger N, R?other K, Drescher B, Sauer C, Zrenner E, Meitinger T, Rosenthal A, Meindl A. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet. 1998 Jul;19(3):260-3.

PubMed ID:

9662399

Night Blindness, Congenital Stationary, CSNB1C

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. The photopic ERG is usually abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision. Nystagmus and photophobia are usually not features. Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies. The amount of pigmentary retinopathy is highly variable.

In this disorder (CSNB1C) the b-wave responses are severely deficient (no scotopic response) and a-waves seem to be normal. Some reduction in central acuity is common. High myopia may be present together with nystagmus and strabismus. In one family, hypoplastic discs and relative thinning of the inner nuclear layer were described in twin brothers. ERG responses suggest loss of ON bipolar cell function similar to that found in patients with GRM6 mutations (CSNB1B; 257270).

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

CSNB1C, or type 1C, is one of four congenital nightblindness disorders with autosomal recessive inheritance. It results from mutations in the TRPM1 (15q13-q14) gene which encodes for a calcium ion channel protein, part of the GRM6 signaling cascade.

Other autosomal recessive CSNB disorders are: CSNB2B (610427), CSNB (unclassified; OMIM number pending), and CSNB1B (257270).

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision. Refractive errors need to be corrected and low vision aids can be helpful for those with some loss of central acuity.

References

Article Title:

Presentation of TRPM1-Associated Congenital Stationary Night Blindness in Children

Miraldi Utz V, Pfeifer W, Longmuir SQ, Olson RJ, Wang K, Drack AV. Presentation of TRPM1-Associated Congenital Stationary Night Blindness in Children. JAMA Ophthalmol. 2018 Mar 8. doi: 10.1001/jamaophthalmol.2018.0185. [Epub ahead of print].

PubMed ID:

29522070

Congenital stationary night blindness with hypoplastic discs, negative electroretinogram and thinning of the inner nuclear layer

Al Oreany AA, Al Hadlaq A, Schatz P. Congenital stationary night blindness with hypoplastic discs, negative electroretinogram and thinning of the inner nuclear layer. Graefes Arch Clin Exp Ophthalmol. 2016 Apr 15. [Epub ahead of print].

PubMed ID:

27084085

The molecular basis of human retinal and vitreoretinal diseases

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75.

PubMed ID:

20362068

Recessive mutations of the gene TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness in humans

Li Z, Sergouniotis PI, Michaelides M, Mackay DS, Wright GA, Devery S, Moore AT, Holder GE, Robson AG, Webster AR. Recessive mutations of the gene TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness in humans. Am J Hum Genet. 2009 Nov;85(5):711-9.

PubMed ID:

19878917

Mutations in TRPM1 are a common cause of complete congenital stationary night blindness

van Genderen MM, Bijveld MM, Claassen YB, Florijn RJ, Pearring JN, Meire FM, McCall MA, Riemslag FC, Gregg RG, Bergen AA, Kamermans M. Mutations in TRPM1 are a common cause of complete congenital stationary night blindness. Am J Hum Genet.2009 Nov;85(5):730-6.

PubMed ID:

19896109

Night Blindness, Congenital Stationary, CSNB1B

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. However, the photopic ERG can be abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision. Nystagmus and photophobia are usually not features. Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies. The amount of pigmentary retinopathy is highly variable.

In this disorder (CSNB1B) the b-wave responses are severely deficient and a-waves seem to be normal. Color vision is normal and refractive errors are unremarkable. Visual acuity ranges from normal to a mild reduction (20/15-20/40). One patient with 20/40 vision has been reported to have bone spicule pigment clumps in the midperiphery. Several patients with subnormal vision have been reported to have nystagmus.

Patients have a distinctive ERG pattern response to scotopic 15-Hz flicker stimuli that suggest that more than two rod neural pathways exist.

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

CSNB1B, or type 1B, is one of four CSNB disorders with autosomal recessive inheritance. It is the result of mutations in the GRM6 gene (5q35) which lead to functional loss of the glutamate receptor.

Other autosomal recessive CSNB disorders are: CSNB2B (610427), CSNB (unclassified; OMIM number pending), and CSNB1C (613216).

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Article Title:

The molecular basis of human retinal and vitreoretinal diseases

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75.

PubMed ID:

20362068

Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6

Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA, Alexander KR, Derlacki DJ, Rajagopalan AS. Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4884-9. Epub 2005 Mar 21.

PubMed ID:

15781871

Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram

Zeitz C, van Genderen M, Neidhardt J, Luhmann UF, Hoeben F, Forster U, Wycisk K, M?degty?degs G, Hoyng CB, Riemslag F, Meire F, Cremers FP, Berger W. Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4328-35.

PubMed ID:

16249515

Night Blindness, Congenital Stationary, CSNB1A

Clinical Characteristics

Ocular Features:

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive. However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB). At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them. All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves. The photopic ERG is usually abnormal to some degree as well and visual acuity may be subnormal. In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB. Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision. Nystagmus and photophobia are usually not features. Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies. The amount of pigmentary retinopathy is highly variable.

CSNB1A, or type 1A, is associated with myopia which ranges from mild to severe. Rod function is completely absent. Nystagmus and strabismus are inconsistent findings. Visual acuity ranges from 20/30 to 20/200. Retinal pigmentation is usually normal in the X-linked forms. Night blindness is more severe in this form than in another X-linked CSNB , type 2A (300071).

Systemic Features:

No systemic disease is associated with congenital stationary night blindness.

Genetics

Congenital stationary night blindness type 1A is an X-linked disorder caused by a mutation in the NYX gene located at Xp11.4. Only males are affected and carrier females do not have clinical disease (although homozygous females with typical findings have been described).

Approximately 45% of X-linked CSNB are of this type while about 55% have another X-linked form known as CSNB2A, or type 2A (300071) resulting from a mutation at Xp11.23. A single patient with high myopia absent night blindness with a mutation in the NYX gene has been reported.

Pedigree:

X-linked recessive, carrier mother

X-linked recessive, father affected

Treatment

Treatment Options:

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Article Title:

A novel missense mutation in the NYX gene associated with high myopia

Yip SP, Li CC, Yiu WC, Hung WH, Lam WW, Lai MC, Ng PW, Fung WY, Chu PH, Jiang B, Chan HH, Yap MK. A novel missense mutation in the NYX gene associated with high myopia. Ophthalmic Physiol Opt. 2013 Feb. [Epub ahead of print].

PubMed ID:

23406521

The molecular basis of human retinal and vitreoretinal diseases

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75.

PubMed ID:

20362068

Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness

Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AA, Prinsen CF, Polomeno RC, Gal A, Drack AV, Musarella MA, Jacobson SG, Young RS, Weleber RG. Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat Genet. 2000 Nov;26(3):319-23.

PubMed ID:

11062471

Evidence for genetic heterogeneity in X-linked congenital stationary night blindness

Boycott KM, Pearce WG, Musarella MA, Weleber RG, Maybaum TA, Birch DG, Miyake Y, Young RS, Bech-Hansen NT. Evidence for genetic heterogeneity in X-linked congenital stationary night blindness. Am J Hum Genet. 1998 Apr;62(4):865-75.

PubMed ID:

9529339

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