night blindness

Usher Syndrome Type II

Clinical Characteristics

Ocular Features

Retinitis pigmentosa is clinically similar to that of nonsyndromal RP and produces symptoms of nightblindness by adolescence.  The ERG is severely reduced and visual fields are constricted.  Rods seem to be more severely affected than cones.  A loss of thickness in the outer nuclear layer in USH2C and USH2A types has been described.  The fundus often contains patches of hyperfluorescence which become larger and often coalesce in older patients.  The retinal disease is progressive but more slowly than in type I.  Eventually by the 4th to 5th decades the visual field is constricted to 5-10 degrees.  It can result in blindness.  Cataracts are common and some patients have cystic changes in the macula.

Systemic Features

The hearing deficit in type II can be described as hearing loss rather than deafness as found in type I.  Usually high frequencies are impacted more severely than lower frequencies producing a characteristic ‘sloping’ audiogram.  The hearing loss is present at birth and progressive, at least in some individuals.  Speech usually develops.  Vestibular dysfunction is not a feature of type II Usher syndrome.  The mental changes observed in type I do not occur in type II.

Genetics

Like other forms of Usher syndrome, type II is inherited in an autosomal recessive pattern.  Like type I, it is genetically heterogeneous and mutations in at least 4 genes seem to be responsible.  Three have been identified: type IIA (USH2A; 276901) results from mutations in the USH2A gene on chromosome 4 (1q41), type IIC (USH2D; 605472) from mutations in GPR98 (5q14), and type IID (USH2D; 611383) is caused by mutations in the DFNB31 gene (9q32-q34).  Type IIB (USH2B) results from mutations in a locus mapped to 3p24.2-p23 but the gene has not been identified.  Clinical features are sufficiently similar so that these are discussed here as a single entity.

This is the most common of the three types of Usher syndrome.  Type I Usher syndrome (276900) results from mutations in at least 7 genes and type III (276902) is caused by a mutations in the CLRN1 gene.

Treatment Options

Hearing aids can be helpful and speech therapy may be highly beneficial for the development of speech.  Cochlear implants have been suggested for older persons who have the more severe hearing loss.  Auditory testing should be done shortly after birth and the hearing loss monitored periodically.

References

Blanco-Kelly F, Jaijo T, Aller E, Avila-Fernandez A, López-Molina MI, Giménez A, García-Sandoval B, Millán JM, Ayuso C. Clinical Aspects of Usher Syndrome and the USH2A Gene in a Cohort of 433 Patients. JAMA Ophthalmol. 2014 Nov 6. [Epub ahead of print].

PubMed ID: 
25375654

Schwartz SB, Aleman TS, Cideciyan AV, Windsor EA, Sumaroka A, Roman AJ, Rane T, Smilko EE, Bennett J, Stone EM, Kimberling WJ, Liu XZ, Jacobson SG. Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype. Invest Ophthalmol Vis Sci. 2005 Feb;46(2):734-43.

PubMed ID: 
15671307

Iannaccone A, Kritchevsky SB, Ciccarelli ML, Tedesco SA, Macaluso C, Kimberling WJ, Somes GW. Kinetics of visual field loss in Usher syndrome Type II. Invest Ophthalmol Vis Sci. 2004 Mar;45(3):784-92.

PubMed ID: 
14985291

Usher Syndrome Type I

Clinical Characteristics

Ocular Features

The fundus dystrophy of retinitis pigmentosa in Usher syndrome is indistinguishable from isolated retinitis pigmentosa.   Night blindness begins by about 10 years of age and the ERG by that time is often markedly diminished or absent.  Patches of hyperfluorescence are seen in younger individuals and these enlarge and coalesce with age.  Tunnel vision occurs early as the peripheral visual field is constricted to 5-10 degrees by midlife.  The retinal disease is progressive and blindness may be the final result.

Systemic Features

Type I Usher syndrome is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to retinitis pigmentosa.  Vestibular areflexia is virtually complete and constitutes a defining feature.  Ataxic gait disturbances are common secondary to labyrinthine dysfunction and many children do not walk until 18-24 months of age.  Sitting alone may also be delayed.  Sperm motility is abnormal which is likely the basis for reduced fertility in male patients.  An abnormal exoneme morphology from ciliated progenitors is likely the common basis for these clinical findings.  MRI imaging has found a significant decrease in intracranial volume and brain size.  About 1 in 4 children have behavioral problems or psychosocial difficulties.

Genetics

Type I Usher syndrome is an autosomal recessive genetically heterogeneous disorder as mutations in at least 8 genes produce a similar disease.  These are: MYO7A (276900) at 11q13.5 causing USH1B (USH1A is now considered to be the same), USH1C at 11p15.1 causing USH1C (276904), CDH23 at 10q21-q22, causing USH1D (601067), PCDH15 at 10q21.1 causing USH1F (602083), and USH1G at 17q24-25 causing USH1G (606943).  Mutations in as yet unnamed genes in loci at 21q21 (USH1E; 602097), 10p11.21-q21.1 (USH1K), and 15q22-q23 (USH1H; 612632) may also cause this type I phenotype. They are discussed here as a single entity designated type I since the clinical features of each are indistinguishable.'

A varant of USH1C resulting from homozygous deletions in 11p15-p14, known as homozygous 11p15-p14 deletion syndrome, has the additional feature of severe hyperinsulinemia due to the involvement of ABCC8 and KCNJ11 genes (606528).

Clinical differences have led to the categorization of three types of Usher syndrome:  type I described here, type II (276901) caused by mutations in at least 4 genes, and type III (276902) caused by mutations in CLRN1.

Treatment Options

At-risk infants should have hearing evaluations as soon as possible after birth.  Assistive hearing devices are of little benefit.  Unless cochlear implants are placed in young children, speech may not develop.  Extra precautions during physical activities such as swimming, bicycling, and night-time driving are highly recommended. Speech therapy and low vision aids can be beneficial.

References

Blanco-Kelly F, Jaijo T, Aller E, Avila-Fernandez A, López-Molina MI, Giménez A, García-Sandoval B, Millán JM, Ayuso C. Clinical Aspects of Usher Syndrome and the USH2A Gene in a Cohort of 433 Patients. JAMA Ophthalmol. 2014 Nov 6. [Epub ahead of print].

PubMed ID: 
25375654

Al Mutair AN, Brusgaard K, Bin-Abbas B, Hussain K, Felimban N, Al Shaikh A, Christesen HT. Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes. Diabetes Care. 2012 Nov 12. [Epub ahead of print].

PubMed ID: 
23150283

Jaworek TJ, Bhatti R, Latief N, Khan SN, Riazuddin S, Ahmed ZM. USH1K, a novel locus for type I Usher syndrome, maps to chromosome 10p11.21-q21.1. J Hum Genet. 2012 Jun 21. doi: 10.1038/jhg.2012.79. [Epub ahead of print].

PubMed ID: 
22718019

Ahmed ZM, Riazuddin S, Riazuddin S, Wilcox ER. The molecular genetics of Usher syndrome. Clin Genet. 2003 Jun;63(6):431-44. Review.

PubMed ID: 
12786748

Smith RJ, Berlin CI, Hejtmancik JF, Keats BJ, Kimberling WJ, Lewis RA, Möller CG, Pelias MZ, Tranebjaerg L. Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium. Am J Med Genet. 1994 Mar 1;50(1):32-8.

PubMed ID: 
8160750

Peroxisome Biogenesis Disorder 1B (neonatal adrenoleukodystrophy)

Clinical Characteristics

Ocular Features

This peroxisomal disorder presents in the first year of life with both systemic and ocular features.  Night blindness is the major ocular feature and at least some have optic atrophy similar to the adult form.  Central acuity is reduced secondary to macular degeneration.  A pigmentary retinopathy is frequently present and often follows the appearance of whitish retinal flecks in the midperipheray.  Nystagmus and cataracts are common features.  Reduction or absence of ERG responses can be used in young children to document the retinopathy.  Blindness and deafness commonly occur in childhood.

Systemic Features

This disorder is classified as a leukodystrophy, or disease of white matter of the brain, associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be early diagnostic features as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported.  The ears are low-set and epicanthal folds are present.  The teeth are abnormally large and often have yellowish discoloration.  Postural unsteadiness is evident when patients begin walking.  Diagnosis can be suspected from elevated serum phytanic and pipecolic acid (in 20% of patients) or by demonstration of decreased phytanic acid oxidation in cultured fibroblasts.  Other biochemical abnormalities such as hypocholesterolemia, and elevated very long chain fatty acids and trihydroxycholestanoic acid are usually present.  Anosmia, developmental delays, and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common.

Genetics

This is a genetically heterogeneous disorder of peroxisome biogenesis caused by mutations in at least three genes, PEX1 (7q21-q22), PEX2 (8q21.1), and PEX6 (22q11-21).  Each is inherited in an autosomal recessive pattern.  The mechanism of disease is different from the classic or adult Refsum disorder (266500) and some have debated whether the term ‘infantile Refsum disease’ is appropriate.

This disorder shares some clinical features with other peroxisomal disorders such as Zellweger syndrome (214100) and rhizomelic chondrodysplasia punctata (215100).  Zellweger syndrome (214100), neonatal adrenoleukodystrophy and infantile Refsum disease (601539) are now considered to be peroxisomal biogenesis or Zellweger spectrum disorders.

Treatment Options

No effective treatment is known.

References

Goez H, Meiron D, Horowitz J, Schutgens RH, Wanders RJ, Berant M, Mandel H. Infantile Refsum disease: neonatal cholestatic jaundice presentation of a peroxisomal disorder. J Pediatr Gastroenterol Nutr. 1995 Jan;20(1):98-101.

PubMed ID: 
7533834

Wanders RJ, Saelman D, Heymans HS, Schutgens RB, Westerveld A, Poll-Thé BT, Saudubray JM, Van den Bosch H, Strijland A, Schram AW, et al. Genetic relation between the Zellweger syndrome, infantile Refsum's disease, and rhizomelic chondrodysplasia punctata. N Engl J Med. 1986 Mar 20;314(12):787-8.

PubMed ID: 
2419755

Refsum Disease, Adult

Clinical Characteristics

Ocular Features

A retinitis pigmentosa-like retinopathy is the major ocular manifestation of this disease.  There is typical night blindness and visual field constriction.   Rod ERG responses are usually subnormal.  However, central acuity is also reduced due to a degenerative maculopathy.   Cataracts and optic atrophy are common.  The macula may undergo progressive degeneration and optic atrophy is not uncommon.  Some patients have defective pupillary responses.

Systemic Features

Onset of symptoms is usually late in the first decade and sometimes into the third decade.  There is usually a polyneuropathy with impaired motor reflexes and paresis in the limbs.  A progressive sensorineural hearing loss occurs in many patients.  Sensory deficits also occur.  Some have ataxia and skin changes of ichthyosis.  Anosmia is a near universal feature.  Heart failure may occur and cardiac abnormalities such as conduction defects can occur.  A variety of skeletal abnormalities such as pes cavus, short fourth metatarsals, and evidence of epiphyseal dysplasia have been reported.  There is considerable clinical heterogeneity even within families.

Phytanic acid oxidase activity as measured in fibroblasts is often low while serum phytanic acid is increased.  The cerebrospinal fluid contains increased protein but no increase in cells.

Genetics

This disorder results from mutations in the PHYH (PAHX) gene (10pter-p11.2) encoding phytanoyl-CoA hydroxylase, or, more rarely in PEX7 (6q22-q24) encoding peroxin-7 resulting in an uncommon condition (10% of cases) sometimes called adult Refsum disease-2. 

Mutations in the latter gene also cause rhizomelic chondrodysplasia punctata type 1 (215100) which does not have all of the neurological features or the retinopathy.

There is also so-called infantile form of Refsum disease (266510).

Treatment Options

A diet low in phytanic acid can lead to improvement in the neurologic symptoms such as the ataxia and polyneuropathy but must be instituted in early stages of the disease.  This approach may not be as beneficial for the visual or auditory symptoms.

References

van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR, Wanders RJ. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet. 2003 Feb;72(2):471-7.

PubMed ID: 
12522768

Jansen GA, Hogenhout EM, Ferdinandusse S, Waterham HR, Ofman R, Jakobs C, Skjeldal OH, Wanders RJ. Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease. Hum Mol Genet. 2000 May 1;9(8):1195-200.

PubMed ID: 
10767344

Skjeldal OH, Stokke O, Refsum S, Norseth J, Petit H. Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation. J Neurol Sci. 1987 Jan;77(1):87-96.

PubMed ID: 
2433405

Flecked Retina Syndromes

Clinical Characteristics

Ocular Features

There exist a considerable number of disorders often classified under the heading of ‘flecked retina’ syndrome.  Prior to the modern genomic period, distinctions among them were based on the clinical picture, functional abnormalities, and electrophysiological studies.  The nosology is becoming clearer as more individuals are genotyped.  We can expect further discrimination of these disorders in the near future.

White or yellow discrete dots are found throughout the fundus.  These are most dense in the midperiphery RPE and the macula is generally not involved.  This is most common in patients with fundus albipunctatus who have a nonprogressive disease.  Stationary night blindness is the predominant symptom.  However, patients with mutations in RDH5 may have more serious cone involvement and progressive macular disease.  Visual acuity varies from near normal to severe loss.  Photopic ERGs may be normal but only low scotopic responses can be recorded in such patients.  Cone dysfunction is more characteristic of older patients.

Systemic Features

No systemic disease is associated with these syndromes.

Genetics

These disorders are sometimes grouped into the category of 'flecked retina disease'.

Autosomal dominant inheritance is typical for fundus albipunctatus (136880) resulting from mutations in the RDS (PRPH2) gene (6p21.1-cen).

Autosomal recessive fundus albipunctatus (136880) is caused by mutations in RDH5 (12q13-q14) and sometimes in RLBP1 (15q26.1).

Retinitis punctata albescens (136880) and fundus albipunctatus (136880) may both be caused by mutations in RLBP1 (15q26.1).  In a consanguineous family in which younger individuals (aged 3-20 years) had signs of fundus albipunctatis, older individuals in the fourth and fifth decades of life had features of retinitis punctata albescens (136880).  Homozygous mutations in RLBP1 were found in all individuals.  Homozygous mutations in the same gene are also responsible for Bothnia type retinal dystrophy (607475).

Familial Benign Fleck Retina (228980) is characterized by a normal ERG and normal vision. The macula is spared from the white/yellow flecks located behind retinal vessels. Autofluorescence is present and the fluorescein angiogram shows irregular hypofluorescence.  Nothing is known about the mutation but the clinical condition is inherited in an autosomal recessive pattern.

Some group Stargardt disease (248200), fleck retina of Kandori (228990),  juvenile retinoschisis (312700), and familial benign fleck retina (228980) as well into the category of 'flecked retina disease'.

Other disorders in which retinal flecks may be seen are: spastic paraplegia 15 (270700), hyperoxaluria (259900), Alport syndrome (301050), Bietti-crystalline-corneoretinal-dystrophy (210370 ), Sjogren-Larsson syndrome (270200), pantothenate kinase-associated neurodegeneration (234200), Leber congenital amaurosis (204000), and Bardet-Biedl syndrome (209900),

Treatment Options

Low vision aids may be useful when macular disease is present.  A recent report describes improvement in peripheral fields and rod function following administration of high-dose oral 9-cis-beta-carotene.

References

Ajmal M, Khan MI, Neveling K, Khan YM, Ali SH, Ahmed W, Iqbal MS, Azam M, den Hollander AI, Collin RW, Qamar R, Cremers FP. Novel mutations in RDH5 cause fundus albipunctatus in two consanguineous Pakistani families. Mol Vis. 2012;18:1558-71.

PubMed ID: 
22736946

Rotenstreich Y, Harats D, Shaish A, Pras E, Belkin M. Treatment of a retinal dystrophy, fundus albipunctatus, with oral 9-cis-{beta}-carotene. Br J Ophthalmol. 2010 May;94(5):616-21.

PubMed ID: 
19955196

Walia S, Fishman GA, Kapur R. Flecked-retina syndromes. Ophthalmic Genet. 2009 Jun;30(2):69-75..

PubMed ID: 
19373677

Niwa Y, Kondo M, Ueno S, Nakamura M, Terasaki H, Miyake Y. Cone and rod dysfunction in fundus albipunctatus with RDH5 mutation: an electrophysiological study. Invest Ophthalmol Vis Sci. 2005 Apr;46(4):1480-5.

PubMed ID: 
15790919

Fishman GA, Roberts MF, Derlacki DJ, Grimsby JL, Yamamoto H, Sharon D, Nishiguchi KM, Dryja TP. Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes. Arch Ophthalmol. 2004 Jan;122(1):70-5.

PubMed ID: 
14718298

Nakamura M, Miyake Y. Macular dystrophy in a 9-year-old boy with fundus albipunctatus. Am J Ophthalmol. 2002 Feb;133(2):278-80.

PubMed ID: 
11812441

Katsanis N, Shroyer NF, Lewis RA, Cavender JC, Al-Rajhi AA, Jabak M, Lupski JR. Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1. Clin Genet. 2001 Jun;59(6):424-9. PubMed PMID: 11453974.

PubMed ID: 
11453974

Isaacs TW, McAllister IL, Wade MS. Benign fleck retina. Br J Ophthalmol. 1996 Mar;80(3):267-8. PubMed PMID: 8703867

PubMed ID: 
8703867

Oguchi Disease, Type 2

Clinical Characteristics

Ocular Features

The distinctive feature of Oguchi disease is the peculiar and distinctive discoloration of the fundus under various light conditions, known as the Mizuo phenomenon.  Typically, the fundus assumes a golden or gray-white coloration under light adapted conditions but this disappears during acute dark adaptation and only reappears after prolonged time spent in darkness.  Rod dark adaptation is markedly delayed while that of cones is normal.  Single flash cone and 30Hz flicker responses are markedly reduced.  Visual acuity, visual fields and color vision are all normal.   A- and b-waves on single flash ERG are decreased or absent under lighted conditions but increase after prolonged dark adaptation.  Night blindness is present from birth without progression.

Systemic Features

No systemic abnormalities are associated with Oguchi disease.

Genetics

Oguchi type 2 disease is an autosomal recessive condition caused by mutations in the rhodopsin kinase (GRK1) gene (13q34) whose product works with arrestin in turning off rhodopsin after light activation as part of the dark adaptation mechanism.

Oguchi type 1 disease (258100) is a similar form of congenital stationary nightblindness caused by mutations in the SAG gene.

Treatment Options

No treatment is available.

References

Yamamoto S, Sippel KC, Berson EL, Dryja TP. Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness. Nat Genet. 1997 Feb;15(2):175-8.

PubMed ID: 
9020843

Hayashi T, Gekka T, Takeuchi T, Goto-Omoto S, Kitahara K. A novel homozygous GRK1 mutation (P391H) in 2 siblings with Oguchi disease with markedly reduced cone responses. Ophthalmology. 2007 Jan;114(1):134-41.

PubMed ID: 
17070587

Oguchi Disease, Type 1

Clinical Characteristics

Ocular Features

The distinctive feature of Oguchi disease is the peculiar and distinctive discoloration of the fundus under various light conditions, known as the Mizuo phenomenon.  Typically, the fundus assumes a golden or gray-white coloration under light adapted conditions but this disappears during acute dark adaptation and only reappears after prolonged time spent in darkness.  Rod dark adaptation is markedly delayed while that of cones is normal.  Visual acuity, visual fields and color vision are all normal.   A- and b-waves on single flash ERG are decreased or absent under lighted conditions but increase after prolonged dark adaptation.  Night blindness is present from birth without progression.

Systemic Features

No systemic abnormalities are associated with Oguchi disease.

Genetics

Oguchi type 1 disease is an autosomal recessive condition caused by mutations in the arrestin (SAG) gene (2q37.1) whose product is an intrinsic photoreceptor protein that participates in the recovery phase of light transduction.

Oguchi disease type 2 (613411), a similar form of congenital stationary night blindness, is caused by mutations in the GRK1 gene.  Genotyping is required to distinguish between the two types.

Treatment Options

No treatment is available.

References

Fuchs S, Nakazawa M, Maw M, Tamai M, Oguchi Y, Gal A. A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nat Genet. 1995 Jul;10(3):360-2.

PubMed ID: 
7670478

Maw MA, John S, Jablonka S, Müller B, Kumaramanickavel G, Oehlmann R, Denton MJ, Gal A. Oguchi disease: suggestion of linkage to markers on chromosome 2q. J Med Genet. 1995 May;32(5):396-8.

PubMed ID: 
7616550

Bietti Crystalline Corneoretinal Dystrophy

Clinical Characteristics

Ocular Features

The retina contains refractile glistening intraretinal crystals at all levels and choroidal vessels are said to be sclerosed.  The RPE atrophies and often forms pigment clumps.  The yellow-white crystals are also seen in the peripheral cornea and in the limbus.  Symptoms of night blindness and early vision loss begin about the third decade.  Night blindness is progressive as is the narrowing of the visual fields but this is highly variable between patients.  The visual field may show paracentral scotomas at some stage.  Central acuity can be normal until late in the disease when it becomes markedly impaired. Legal blindness can occur by the 5th decade of life. 

The ERG may show lack of rod and cone responses late in the disease and color vision may be lost.  However, the ffERG and mfERGs show decreases in amplitude of scotopic and photopic responses in all patients, even younger ones.  The EOG becomes abnormal in late stages.  The degree of involvement may be asymmetrical.  Complex lipid inclusions can be seen histologically in choroidal, conjunctival and skin fibroblasts, as well as in keratocytes and lymphocytes.

Crystalline deposits have been detected mostly in the proximal portions of RPE cells adjacent to degenerated retinal  areas.  Most common are circular hyperrefractive structures in the outer nuclear layer adjacent to areas of degeneration.  Some patients have cystoid macular edema.

Systemic Features

No other organ disease has been reported.

Genetics

This is an autosomal recessive disorder caused by mutations in the CYP4V2 gene (4q35.1) which may be involved in fatty acid metabolism.

Treatment Options

No treatment beyond low vision aids is available.

References

Saatci AO, Doruk HC, Yaman A. Cystoid Macular Edema in Bietti's Crystalline Retinopathy. Case Rep Ophthalmol Med. 2014.  Epub 2014 May 11.

PubMed ID: 
24949209

Okialda KA, Stover NB, Weleber RG, Kelly EJ. Bietti Crystalline Dystrophy.
2012 Apr 12. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors.
GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.
Available from http://www.ncbi.nlm.nih.gov/books/NBK91457/.
 

PubMed ID: 
22497028

Kojima H, Otani A, Ogino K, Nakagawa S, Makiyama Y, Kurimoto M, Guo C, Yoshimura N. Outer retinal circular structures in patients with Bietti crystalline retinopathy. Br J Ophthalmol. 2011 Jul 29. [Epub ahead of print]

PubMed ID: 
21803923

Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, Hayakawa M, Kanai A, Shy Chen M, Alan Lewis R, Heckenlively J, Weleber RG, Traboulsi EI, Zhang Q, Xiao X, Kaiser-Kupfer M, Sergeev YV, Hejtmancik JF. Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. Am J Hum Genet. 2004 May;74(5):817-26. Epub 2004 Mar 23.

PubMed ID: 
15042513

Sen P, Ray R, Ravi P. Electrophysiological findings in Bietti's crystalline dystrophy. Clin Exp Optom. 2011 May;94(3):302-8. Epub 2011 Apr 13

PubMed ID: 
21488952

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 9 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them.  All are caused by 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.  All individuals with congenital nightblindness were homozygous for a missense mutation in GNAT1 while unaffected persons were heterozygous.

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.

Treatment Options

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

References

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

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

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 9 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them.  All are caused by 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.

Treatment Options

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

References

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

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