RLBP1

Retinal Dystrophy, Newfoundland Type

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity, mostly age-dependent.  Night blindness can occur in early childhood but usually later even though scotopic responses can be undetectable in the first decade of life while photopic responses are reduced on the ERG at all ages.  Both rod and cone responses may be extinguished in later life.  Visual acuity can be decreased beginning in early childhood and legal blindness usually occurs by the second or third decade of life.  However, the loss of vision continues to progress and severe vision loss to finger-counting may be present in older individuals.  A scallop-bordered lacunar atrophy may be seen in the midperiphery.  The macula is only mildly involved by clinical examination although central retinal thinning is seen in all cases.  Dyschromatopsia is mild early and usually becomes more severe.  The visual fields are moderately to severely constricted although in younger individuals a typical ring scotoma is present.  The peripheral retina contains ‘white dots’ and often resembles the retinal changes seen in retinitis punctate albescens.

Systemic Features: 

None reported.

Genetics

Homozygous mutations in the RLBP1 gene (15q26.1) are responsible for this disorder.  Homozygous mutations in RLBP1 have also been found among patients with fundus albipunctatus (136880), retinitis punctata albescens, and in Bothnia type retinal dystrophy (607475),

NFRCD clinically resembles Bothnia type retinal dystrophy (607475) which likewise results from mutations in the RLBP1 gene but the maculae appear normal or have only a mild ‘beaten-bronze’ atrophy.

See Flecked Retina entry for somewhat similar conditions.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Retinitis Punctata Albescens

Clinical Characteristics
Ocular Features: 

Uniform white dots are symmetrically distributed in the midportion and periphery of the retina but the central portion of the macula is usually relatively spared in early stages of the disease.  These flecks are present in the first decade of life increasing in density and covering larger areas of the retina in older individuals.  Difficulties with night vision are also noted early and visual acuity may be compromised, in the range of 20/40.  By the fifth and sixth decades there may be retinal pigment atrophy in the midperiphery and this eventually progresses to geographic atrophy of the macular RPE as the visual field becomes more constricted.  The fundus in older individuals resembles that seen in retinitis pigmentosa with retinal vascular attenuation, frank bone spicule pigmentation, macular disease, and pallor of the optic nerves with significant loss of vision.  The ERG shows reduction in scotopic responses and mild reductions in photopic amplitudes.

This form of flecked retina is sometimes considered to be a variant of fundus albipunctatus (136880).  In favor of this argument are the observations in families in which some young members have the fundus picture of fundus albipunctatus (136880) while older ones with more advanced disease have all of the features of retinitis punctata albescens.  Also supportive is the fact that mutations in RLBP1 have been identified in both conditions.  

However, many individuals with fundus albipunctatus (136880) are described as having a stable disease with night blindness as the major symptom while many patients reported with retinitis albescens clearly have a more progressive and more serious disease with a fundus picture in late stages resembling retinitis pigmentosa.  The relationship of these two conditions should become clearer once we learn more about the natural history of these rare disorders.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in RLBP1 (15q26.1).  Parental consanguinity is frequently present.  Mutations in the same gene are also responsible for Bothnia type retinal dystrophy (607475), fundus albipunctatus (136880), and occasional patients with classical retinitis pigmentosa. 

Some authors consider retinitis punctata albescens to have an autosomal dominant pattern of transmission, perhaps based on the presence of white spots in the retina of parents.  However, heterozygotes are always asymptomatic.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

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

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

Fundus Albipunctatus

Clinical Characteristics
Ocular Features: 

This disorder is often considered to belong to the category of retinal disease known as flecked retina syndrome.  Further, the nomenclature is not standardized and varying names have been attached to the more or less characteristic fundus picture consisting of uniformly distributed small yellow-white dots in the retina.  These tend to be concentrated in the midperiphery.  The macula usually is not involved in young people although ERG evidence suggests some worsening of cone dysfunction with age and central acuity may be decreased in midlife.  Frank macular degeneration has been seen clinically .  Delayed dark adaptation can be demonstrated with delays in recovery of rod and cone function.  Patients complain of night blindness beginning in childhood with little evidence of progression.

The disease known as retinitis punctata albescens (136880) may or may not be a unique disorder.  It is sometimes grouped with fundus albipunctatus while others consider it to be a separate entity.  Evidence for its uniqueness is based on the progressive nature of field loss and the presence of pigmentary changes and retinal vascular attenuation which are not found in fundus albipunctatus.  Further, the scotopic ERG waveforms usually do not regenerate.  More discriminating studies, especially genotyping, will likely provide additional information.  It would also be useful to have additional follow-up information on families. 

Systemic Features: 

No systemic disease is associated.

Genetics

Fundus albipunctatus is a genetically heterogeneous disorder.  Mutations in two genes, PRPH2 (6p21.1) and RDH5 (12q13.2) have been found among families.  The inheritance pattern for families with mutations in PRPH2 is consistent with autosomal dominant inheritance while mutations in RDH5 result in an autosomal recessive pattern.  Mutations in RLBP1 have also been found in some families.

Gene studies so far have not been helpful in discriminating between fundus albipunctatus and retinitis punctata albescens (136880).  For example, RLBP1 mutations have been identified among members of the same kindred having the clinical diagnosis of retinitis punctata albescens (136880) among older individuals while younger patients had features of fundus albipunctatus.  Further, the latter disorder has also been described among families with mutations in PRPH2 and RHO hinting at further genetic heterogeneity.

A similar clinical picture may be seen in Bietti crystalline corneoretinopathy (210370), Bardet-Biedl syndrome (209900), and hyperoxaluria (259900).  More information on flecked retina syndromes may be found at Flecked Retina Syndromes.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available to restore full receptor cell function.  However, high oral doses of beta-carotene may lead to an improvement in night blindness. Low vision aids could be beneficial when central acuity is damaged.

References
Article Title: 

Retinal Dystrophy, Bothnia Type

Clinical Characteristics
Ocular Features: 

Night blindness occurs from early childhood when the fundus still appears normal.  However, rod responses may be absent from ERG recordings even in the first decade and this is followed by loss of cone responses in older individuals. Rod responses can recover after prolonged dark adaptation but cone function does not recover.  Multifocal ERGs can detect early deterioration of the macula while vision and the appearance of the macula are still normal.

Pigment deposition can sometimes be seen in the retina and the retinal blood vessels may be attenuated.  In young adults the fundus may have the appearance of retinitis albescens but eventually changes resembling central areolar atrophy develop in the macula.  Retinal thinning in the fovea and parafoveal areas has been described.  Progressive loss of vision leads to legal blindness in early adulthood.  The peripheral retina undergoes degenerative changes as well.

Systemic Features: 

No extraocular abnormalities have been reported.

Genetics

Homozygous mutations in the RLBP1 gene (15q26.1) have been identified in patients with Bothnia retinal dystrophy.  The protein product is essential to the proper function of both rod and cone photoreceptors.  When defective the normal cycling of retinoids between RPE cells and photoreceptors is disrupted, thereby negatively impacting what is sometimes called the 'visual cycle'. 

This rod-cone dystrophy has a high prevalence in northern Sweden.

Homozygous mutations in RLBP1 have also been found among patients in fundus albipunctatus (136880), retinitis punctata albescens, and in Newfoundland type retinal dystrophy (607476).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None has been reported. Tinted lenses can be helpful.

References
Article Title: 

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 and 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 severe in 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) and for the Newfoundland type of retinal dystrophy (607476).

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),

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
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
Article Title: 

Flecked-retina syndromes

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

PubMed ID: 
19373677

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

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

Benign fleck retina

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

PubMed ID: 
8703867
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