night blindness

Congenital Disorder of Glycosylation, Type Ia

Clinical Characteristics
Ocular Features: 

Strabismus, roving eye movements (and nystagmus), and visual inattention are found in nearly all patients. Esotropia with defective abduction seems to be the most common oculomotor finding and may be present at birth.  Cataracts, ocular colobomas, oculomotor apraxia, disc pallor, and glaucoma have also been reported.  Vision is always subnormal. Reports of ocular disease before modern genotyping are not specific to the subtypes of CDG I now recognized.

This is a congenital, progressive disorder of photoreceptor degeneration with a later onset of progressive pigmentary retinopathy.  It is described in some cases as a typical retinitis pigmentosa.  The ERG is abnormal in all patients even if the pigmentary pattern is atypical for RP.  Rod responses are usually absent while the cone b-wave implicit time is delayed.  The degree of photoreceptor damage is variable, however.  Extended retinal function among younger patients suggest that the ‘on-pathway’ evolving synapses in the outer plexiform layer among photoreceptors, bipolar cells, and horizontal cells is severely dysfunctional.

Systemic Features: 

This is a multisystem disorder, often diagnosed in the neonatal period by the presence of severe encephalopathy with hypotonia, hyporeflexia, and poor feeding.  Failure to thrive, marked psychomotor retardation, delayed development, growth retardation, and ataxia become evident later in those who survive.  Cerebellar and brainstem atrophy with a peripheral neuropathy can be demonstrated during late childhood.  Some older patients have a milder disease, often with muscle atrophy and skeletal deformities such as kyphoscoliosis and a fusiform appearance of the digits.  Maldistribution of subcutaneous tissue is often seen resulting in some dysmorphism, especially of the face.  Hypogonadism and enlargement of the labia majora are commonly present.  Some patients have evidence of hepatic and cardiac dysfunction which together with severe infections are responsible for a 20% mortality rate in the first year of life.

Genetics

This is one of a group of genetically (and clinically) heterogeneous autosomal recessive conditions caused by gene mutations that result in enzymatic defects in the synthesis and processing of oligosaccharides onto glycoproteins. This type (Ia) is the most common.   The mutation lies in the PMM2 gene (16p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Most children require tube feeding with nutritional supplements.  The risk of systemic infections is high.  Those patients who survive into the second decade and beyond may require orthopedic procedures and are confined to wheelchairs.  Physical, occupational, and speech therapy along with parental support are important.

References
Article Title: 

Retinitis Pigmentosa 1

Clinical Characteristics
Ocular Features: 

Night blindness, the predominant presenting symptom, is often noted in the first decade of life but may not be a significant complaint until the third decade.  Concentric peripheral field loss likewise follows a similar timeline.  ERG responses progressively decrease in amplitude and may become undetectable in the second decade.  The retinal disease progresses relentlessly, albeit slowly, as the result of photoreceptor degeneration and most patients have severe visual handicaps by midlife but there is considerable clinical variation.  The pigmentary retinopathy is typical for classical retinitis pigmentosa with vascular attenuation, perivascular bone-spicule pigment clumping, optic atrophy, and generalized retinal atrophy with relative sparing of the macula early in the disease.  Lens opacities in late stages of the disease are common.

Systemic Features: 

No systemic disease is associated with the ocular disorder caused by mutations in RP1.

Genetics

Multiple heterozygous, homozygous, and compound heterozygous mutations in the RP1 gene (8q12.1) sometimes called the oxygen-regulated photoreceptor protein 1 or ORP1 gene are responsible for this disorder.  The protein product is active specifically in retinal photoreceptors.  Retinitis pigmentosa 1 is generally considered to be an autosomal dominant disorder and accounts for 5-7% of dominantly inherited RP disease.  However, recent reports suggest that some mutations in RP1 are responsible for familial cases transmitted in an autosomal recessive pattern in which the clinical disease is more severe. 

More than 20 different mutant genes have been associated with autosomal dominant RP but many cases lack a family history suggesting additional genetic heterogeneity remains.  Reduced penetrance and variable expressivity characteristic of genetic disease likely contributes to the clinical heterogeneity as well.  For more about autosomal dominant retinitis pigmentosa, see Retinitis Pigmentosa, AD (180380, 268000).  

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Photoreceptor transplantation has been tried in a number of patients without improvement in central vision or interruption in the rate of vision loss.  Longer term results are needed.  Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice.  High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  Oral acetazolamide can be helpful in reducing macular edema.

Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision at least temporarily.

Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E.

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: 

Chorioretinopathy, Ataxia, and Hypogonadism

Clinical Characteristics
Ocular Features: 

The retinal pigment epithelium changes may be seen as early as the first decade of life with pigment deposition resembling bone spicules.  These changes as well as atrophy of the choriocapillaris are most apparent in the posterior pole and extend into the midperiphery.  Retinal vessels may be attenuated.  Progressive loss of vision and photophobia are the primary ocular symptoms but some color vision may be retained. Night blindness and constricted visual fields are noted by some patients.  The ERG shows subnormal and sometimes absent photopic and scotopic responses.  Nystagmus is present in more than half of individuals. 

Systemic Features: 

Difficulties with balance, intention tremors, and scanning speech are evident in adolescence or early adult life.  Cerebellar ataxia is present in nearly 40 percent of individuals.  However, there is marked variability in the rate of progression.  Many patients have atrophy of the superior and dorsal areas of the cerebellar vermis and atrophy of the cerebellar hemispheres as noted on MRIs. Hypogonadotrophic hypogonadism is a feature with delayed puberty noted in 26 percent.  In the absence of exogenous hormone administration, secondary sexual characteristics fail to develop.

Genetics

Autosomal recessive inheritance has been suggested on the basis of consanguinity in three families, multiple affected sibs born to normal parents, and a 1:1 sex ratio.  Homozygous and compound heterozygous mutations in PNPLA6 (19p13.2) have been found in several patients.

Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Trichomegaly Plus Syndrome (275400), in this database.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The use of appropriate hormones can stimulate the development of normal secondary sexual characteristics and may restore reproductive function.   At least two female patients gave birth to a child following hormone substitution.

Low vision aids could be helpful in selected patients.

References
Article Title: 

Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature

Tarnutzer AA, Gerth-Kahlert C, Timmann D, Chang DI, Harmuth F, Bauer P, Straumann D, Synofzik M. Boucher-Neuhauser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature. J Neurol. 2014 Oct 31. [Epub ahead of print].

PubMed ID: 
25359264

PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum

Synofzik M, Gonzalez MA, Lourenco CM, Coutelier M, Haack TB, Rebelo A, Hannequin D, Strom TM, Prokisch H, Kernstock C, Durr A, Schols L, Lima-Martinez MM, Farooq A, Schule R, Stevanin G, Marques W Jr, Zuchner S. PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2013 Dec 19. [Epub ahead of print].

PubMed ID: 
24355708

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: 

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

Retinitis Pigmentosa with Ataxia

Clinical Characteristics
Ocular Features: 

Pigmentary retinopathy has been noted by 6 months of age. Typical symptoms of retinitis pigmentosa are reported by early childhood.  The visual fields are progressively constricted and a ring scotoma can be plotted.  Night blindness and visual acuity loss are evident in the first decade of life and progressively worsen leading to severe handicaps by the third.  Fundus pigmentation in the midperiphery becomes more prominent and in at least some patients the pattern consists of typical bone spicules.  Cellophane maculopathy has been described.

Systemic Features: 

Proprioceptive deficits and areflexia appear in early childhood and ataxia worsens as individuals mature.  Scoliosis and general weakness and wasting become prominent manifestations.  Sensory neuropathy with loss of vibratory and position sense, astereognosia, and agraphesthesia can become apparent in the first decade of life.  Walking is delayed and gait abnormalities are clearly evident by the second decade leading to orthopedic deformities such as scoliosis.  Unassisted walking becomes impossible.  The intrinsic hand and foot muscles also have mild weakness.  Sural nerve biopsy may reveal loss of large myelinated fibers.  Hyperintense signals in the posterior spinal columns can be seen on MRI.  No anatomic changes have been described in the cerebrum or cerebellum.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in FLVCR1 (1q32.2-q41).  This disorder has some clinical similarities to Biemond 1 syndrome but differs in the inheritance pattern and the molecular basis.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available but physical therapy and low vision aids may improve the quality of life.

References
Article Title: 

Neuropathy, Ataxia, and Retinitis Pigmentosa

Clinical Characteristics
Ocular Features: 

Night blindness and visual field restriction are early symptoms usually in the second decade of life.  The retina may first show a salt-and-pepper pigmentary pattern which later resembles the classic bone-spicule pattern of retinitis pigmentosa with vascular attenuation.  The optic nerve becomes pale and eventually marked optic atrophy develops.  Severe vision loss is evident in young adults and some patients become blind. 

Systemic Features: 

The onset of systemic symptoms such as unsteadiness occurs some time in the second decade of life.  Irritability, delayed development, and psychomotor retardation may be evident in children whereas older individuals can have frank dementia.  The MRI may reveal cerebral and cerebellar atrophy.  Seizures may have their onset by the third decade.  Numbness, tingling and pain in the extremities are common.  EMG and nerve conduction studies can demonstrate a peripheral neuropathy.  Neurogenic muscle weakness can be marked and muscle biopsy may show partial denervation. Some patients have hearing loss.  A few patients have cardiac conduction defects. 

Genetics

This is a mitochondrial disorder with pedigrees showing maternal transmission.  The mutation (8993T-G) occurs in a subunit of mitochondrial H(+)-ATPase or MTATP6.  The amount of heteroplasmy is variable and likely responsible for the clinical heterogeneity in this disorder.  Individuals with more than 90% mutated chromosomes are considered to have a subtype of Leigh syndrome (MILS) with earlier onset (3-12 months of age).  NARP patients usually have 70-80% or less of mutated mitochondria.  The amount of heteroplasmy may vary among tissues. 

Treatment
Treatment Options: 

No treatment is available for this disease but low vision aids can be helpful in early stages of disease.  Recently it has been demonstrated that alpha-ketoglutarate/aspartate application to fibroblast cell cultures can provide some protection from cell death in NARP suggesting a potential therapeutic option. 

References
Article Title: 

Retinopathy of NARP syndrome

Kerrison JB, Biousse V, Newman NJ. Retinopathy of NARP syndrome. Arch Ophthalmol. 2000 Feb;118(2):298-9.

PubMed ID: 
10676807

Jalili Syndrome

Clinical Characteristics
Ocular Features: 

Symptoms of photophobia and reduced vision are present in the first years of life.  Pendular nystagmus is common.  Color vision is defective and is characterized by some as a form of achromatopsia, perhaps better described as dyschromatopsia.  Reduced night vision is noted by the end of the first decade of life.  OCT reveals reduced foveal and retinal thickness.  The macula appears atrophic with pigment mottling and the peripheral retina can resemble retinitis pigmentosa with bone spicule pigment changes.  Retinal vessels may be narrow.  The ERG show reduced responses in both photopic and scotopic recordings.  This form of rod-cone dystrophy is progressive with central acuity decreasing with age. 

Systemic Features: 

The teeth are abnormally shaped and discolored from birth.  The amelogenesis imperfecta consists of hypoplasia and hypomineralization that is present in both deciduous and permanent teeth.  Tooth enamel is mineralized only to 50% of normal and is similar to that of dentine. 

Genetics

This is an autosomal recessive condition caused by mutations in the CNNM4 gene at 2q11.2. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the ocular condition but red-tinted lenses and low vision aids may be helpful.  The teeth require dental repair. 

References
Article Title: 

Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta

Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, Shahrabi M, Heidari M, Aref P, Abbasi M, Michaelides M, Moore AT, Kirkham J, Inglehearn CF. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am J Hum Genet. 2009 Feb;84(2):266-73.

PubMed ID: 
19200525

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