poor vision

Heart and Brain Malformation Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia is the cardinal ocular malformation.  Hypertelorism has been described.  Poor vision without further description has also been reported.   

Systemic Features: 

The ears are low-set, malformed, and posteriorly rotated.  The forehead is prominent and there is usually a wide anterior fontanel.  The nasal bridge is wide and frequently depressed while the lower lip is full and may be everted and split.  The palate is highly arched.  Physical growth is slow.  A ventricular septal defect is often present while the valves are hypoplastic and the aortic arch can be interrupted.

Microcephaly is often present and there may a profound delay in psychomotor development with truncal hypotonia and hyperreflexia in the limbs.   Brain imaging shows generalized atrophy with decreased myelination.  Cerebellar vermis hypoplasia has been reported.  Two of 5 patients were reported to have Dandy-Walker malformations, and a thin corpus callosum.  Seizures may occur.

Genetics

Homozygous mutations in the SMG9 gene (19q13.31) are responsible for this condition so far reported in 5 individuals in two unrelated consanguineous Arab families.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice

Shaheen R, Anazi S, Ben-Omran T, Seidahmed MZ, Caddle LB, Palmer K, Ali R, Alshidi T, Hagos S, Goodwin L, Hashem M, Wakil SM, Abouelhoda M, Colak D, Murray SA, Alkuraya FS. Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice. Am J Hum Genet. 2016 Apr 7;98(4):643-52.

PubMed ID: 
27018474

Foveal Hypoplasia 2

Clinical Characteristics
Ocular Features: 

The cardinal feature in this condition is foveal hypoplasia which is characterized by the lack of a foveal depression and continuity of all neurosensory layers across the foveal area as revealed by OCT.  This is accompanied by poor visual acuity, nystagmus, and strabismus.  Hypopigmentation of the immediate area has also been reported in some patients.  Visual acuity in one study of 9 patients ranged from 20/50 to 20/200.  The ERG and flash VEP can be normal.  Color vision has been described as normal in some individuals.

Dysgenesis of the anterior segment seems to be family-specific and consists of Axenfeld anomaly or embryotoxon.

Systemic Features: 

In most cases the only features are foveal hypoplasia with or without anterior chamber anomalies.  Three affected sisters in one family were reported to have mild developmental delay.

Genetics

Homozygous mutations in SLC38A8 (16q23.3) are responsible for this disorder. 

For a somewhat similar condition of foveal hypoplasia see FVH1 (136520), which is, however, caused by a different mutation and inherited in an autosomal dominant pattern.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no known treatment.

References
Article Title: 

Blue Diaper Syndrome

Clinical Characteristics
Ocular Features: 

A single patient has been reported with microcornea, optic nerve hypoplasia, and 'abnormal' eye movements.  The full ocular phenotype is unknown but 'visual problems' are sometimes mentioned in other reports.

Systemic Features: 

Nephrocalcinosis and blue urine are the major systemic manifestations of blue diaper syndrome.  Symptoms of fever, constipation, poor weight gain, failure to thrive, and irritability can also be part of the syndrome.

Genetics

This is considered an autosomal recessive disorder although an X-linked defect cannot be ruled out since reported patients have been male.  Parental consanguinity is present in some families.  Nothing is known about the mutation or its locus.  Intestinal transport of tryptophan is defective and bacterial degradation results in excessive indole production.  Oxidation in the urine to indigo blue results in the characteristic discoloration.        

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Restriction of dietary tryptophan has been suggested.

References
Article Title: 

Cone-Rod Dystrophies, X-Linked

Clinical Characteristics
Ocular Features: 

Three X-linked forms of progressive cone-rod dystrophies each with mutations in different genes have been identified.  Central vision is often lost in the second or third decades of life but photophobia is usually noted before vision loss.  Cones are primarily involved but rod degeneration occurs over time.  The ERG reveals defective photopic responses early followed by a decrease in rod responses.   All three types are rare disorders affecting primarily males with symptoms of decreased acuity, photophobia, loss of color vision, and myopia.  The color vision defect early is incomplete but progressive cone degeneration eventually leads to achromatopsia.    Peripheral visual fields are usually full until late in the disease when constriction and nightblindness are evident.  The retina may have a tapetal-like sheen.  RPE changes in the macula often give it a granular appearance and there may be a bull's-eye configuration.   Fine nystagmus may be present as well.  The optic nerve often has some pallor beginning temporally.  Carrier females can have some diminished acuity, myopia, RPE changes, and even photophobia but normal color vision and ERG responses at least among younger individuals.

There is considerable variation in the clinical signs and symptoms in the X-linked cone-rod dystrophies among both affected males and heterozygous females.  Visual acuity varies widely and is to some extent age dependent.  Vision can be normal into the fourth and fifth decades but may reach the count fingers level after that. 

Systemic Features: 

None.

Genetics

Mutations in at least 3 genes on the X chromosome cause X-linked cone-rod dystrophy.

CORDX1 (304020) is caused by mutations in an alternative exon 15 (ORG15) of the RPGR gene (Xp11.4) which is also mutant in several forms of X-linked retinitis pigmentosa (300455, 300029).  These disorders are sometimes considered examples of X-linked ocular disease resulting from a primary ciliary dyskinesia (244400).

CORDX2 (300085) is caused by mutations in an unidentified gene at Xq27.  A single family has been reported.

CORDX3 (300476) results from mutations in CACNA1F.  Mutations in the same gene also cause a form of congenital stationary night blindness, CSNB2A (300071).  The latter, however, is a stationary disorder with significant nightblindness and mild dyschromatopsia, often with an adult onset, and is associated with high myopia. Aland Island Eye Disease (300600) is another allelic disorder.   

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no treatment for these dystrophies but red-tinted lenses provide comfort and may sometimes improve acuity to some extent.  Low vision aids can be helpful. 

References
Article Title: 

Blue Cone Monochromacy

Clinical Characteristics
Ocular Features: 

This is usually a stationary cone dysfunction disorder in which the causative mechanism has yet to be worked out.  Typical patients have severe visual impairment from birth and some have pendular nystagmus and photophobia similar to other achromatopsia disorders.  Vision seems to be dependent solely on blue cones and rod photoreceptors.  The ERG always shows relatively normal rod function whereas the cones are usually dysfunctional. 

In some families, however, there is evidence of disease progression with macular RPE changes and myopia.  This has led to the designation of 'cone dystrophy 5' for such cases even though the mutation locus impacts the same cone opsin genes at Xq28 that are implicated in the more typical BCM phenotype.

Systemic Features: 

None.

Genetics

This is an X-linked recessive form of colorblindness in which DNA changes in the vicinity of Xq28 alters the red and green visual pigment cluster genes via recombination or point mutations.  Alternatively, the control locus adjacent to the cluster may be altered.  In either case, the result may be a loss of function of these genes leaving blue-cone monochromacy.

The mutation for cone dystrophy 5 maps to Xq26.1-qter but the locus encompasses the opsin gene complex at Xq28 as well. 

At least a quarter of individuals with blue cone monochromacy, however, do not have mutations in the vicinity of Xq28 suggesting that additional genetic heterogeneity remains.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Low vision aids can be helpful.  Tinted lenses for photophobia allow for greater visual comfort.  A magenta (mixture of red and blue) tint allows for best visual acuity since it protects the rods from saturation while allowing the blue cones to be maximally stimulated. 

References
Article Title: 

X-linked cone dystrophy caused by mutation of the red and green cone opsins

Gardner JC, Webb TR, Kanuga N, Robson AG, Holder GE, Stockman A, Ripamonti C, Ebenezer ND, Ogun O, Devery S, Wright GA, Maher ER, Cheetham ME, Moore AT, Michaelides M, Hardcastle AJ. X-linked cone dystrophy caused by mutation of the red and green cone opsins. Am J Hum Genet. 2010 Jul 9;87(1):26-39.

PubMed ID: 
20579627

Genetic heterogeneity among blue-cone monochromats

Nathans J, Maumenee IH, Zrenner E, Sadowski B, Sharpe LT, Lewis RA, Hansen E, Rosenberg T, Schwartz M, Heckenlively JR, et al. Genetic heterogeneity among blue-cone monochromats. Am J Hum Genet. 1993 Nov;53(5):987-1000.

PubMed ID: 
8213841

Molecular genetics of human blue cone monochromacy

Nathans J, Davenport CM, Maumenee IH, Lewis RA, Hejtmancik JF, Litt M, Lovrien E, Weleber R, Bachynski B, Zwas F, et al. Molecular genetics of human blue cone monochromacy. Science. 1989 Aug 25;245(4920):831-8.

PubMed ID: 
2788922

Bornholm Eye Disease

Clinical Characteristics
Ocular Features: 

This is primarily a disorder of high myopia but with additional features.  The optic nerve head is moderately hypoplastic and RPE throughout the posterior pole is said to be thinner than normal.  The males also have deuteranopia of a stationary nature and the disorder can also be considered a form of stationary cone dysfunction.  Photophobia and nystagmus are not present.  The ERG demonstrates reduced flicker function with abnormal photopic responses.  Myopia is likely congenital as it has been found in children from 1.5-5 years of age.

The original families reported with this disorder originated on the Danish island of Bornholm from which the eponym is derived.  However, a subsequent American family of Danish descent from nearby islands was found but the males were protanopes.  All affected males had a temporal conus of the optic nerve as well as thinning of the RPE in the posterior pole.  Visual acuity ranged from 20/20 to 20/40 with myopia of minus 10-18 diopters.  No macular disease was visible, no vitreous changes were seen, and none of the subjects had a retinal detachment. There was no evidence of progression in clinical signs over a period of 5 years.  The ERG showed normal scotopic rod function but cone responses were abnormal.  All carrier females and unaffected individuals had normal ERGs and color vision. 

Systemic Features: 

No systemic disease has been associated with this disorder. 

Genetics

This is an X-linked disorder that maps to Xq28 but no gene mutation has been identified.  A form of X-linked high myopia (MYP1) (310460) maps to the same region. 

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

X-linked high myopia associated with cone dysfunction

Young TL, Deeb SS, Ronan SM, Dewan AT, Alvear AB, Scavello GS, Paluru PC, Brott MS, Hayashi T, Holleschau AM, Benegas N, Schwartz M, Atwood LD, Oetting WS, Rosenberg T, Motulsky AG, King RA. X-linked high myopia associated with cone dysfunction. Arch Ophthalmol. 2004 Jun;122(6):897-908.

PubMed ID: 
15197065

X-linked myopia: Bornholm eye disease

Schwartz M, Haim M, Skarsholm D. X-linked myopia: Bornholm eye disease. Linkage to DNA markers on the distal part of Xq. Clin Genet. 1990 Oct;38(4):281-6.

PubMed ID: 
1980096

X-linked myopia in Danish family

Haim M, Fledelius HC, Skarsholm. X-linked myopia in Danish family. Acta Ophthalmol (Copenh). 1988 Aug;66(4):450-6.

PubMed ID: 
3264103

Colorblindness-Achromatopsia 4

Clinical Characteristics
Ocular Features: 

The ocular phenotype in ACHM4 is similar to that of other forms of achromatopsia.  Nystagmus, poor visual acuity, photophobia, and defects in color vision are usually present.  Some subjects, however, retain some color discrimination, a condition referred to as incomplete achromatopsia.  The ERG documents the absence of cone function but normal rod responses.  The retina appears normal clinically.

Few families have been reported and the complete phenotype remains undocumented.  For example, it has been reported that visual acuity weakens with age in some patients although it is uncertain if this is true of all cases. 

Systemic Features: 

No systemic abnormalities are associated. 

Genetics

This is an autosomal recessive disorder caused by mutations in GNAT2 located at 1p13.  These mutations account for less than 2% of achromatopsia cases.  The majority are caused by mutations in CNGA3 (25%), responsible for ACHM2 (216900) and CNGB3 (50%), causing ACHM3 (262300).  Mutations in PDE6C (613093 ) causing ACHM5 are responsible for less than 2%. No doubt others will be found as many cases do not have mutations in these genes. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder but tinted lenses and low vision aids can be helpful.  Red contact lenses can reduce the photophobia and may improve vision. 

References
Article Title: 

Nystagmus 1, Congenital, X-linked

Clinical Characteristics
Ocular Features: 

Congenital nystagmus is a feature of numerous ocular and systemic disorders.  Isolated idiopathic congenital nystagmus (CN), however, refers to a diverse group of abnormal eye movements which are identified usually in the first 6 months of life when no other ocular abnormalities are present.  Horizontal eye movements are typical, but vertical and rotary eye movements have also been reported.  If the nystagmus is horizontal, the eye movement is usually "to-and-fro".   In general, as the patient gets older, the amplitude of the nystagmus decreases and the frequency of the nystagmus increases, particularly when the patient tries to fixate or look directly at an object. This nystagmus can increase in size and frequency when the patient is tired, sick, or fatigued.  Some very young patients are noted to have head nodding or head shaking, but these usually disappear over time. Vision is reduced and varies through the day. Balance may also be affected.  Many patients have a "null point" where the eye movement is reduced and vision is improved.  They may alter their head position in an effort to maximize their acuity.

Strabismus and amblyopia often develop.

Systemic Features: 

No consistent systemic abnormalities have been reported.

Genetics

Different heritable patterns of idiopathic congenital nystagmus, including autosomal dominant and recessive, and X-linked recessive, have been found.  A variety of mutations in the FRMD7 (Xq26.2) gene (containing 12 exons) have been identified in many families with an X-linked recessive pattern. 

Another mutation associated with X-linked congenital nystagmus is GPR143 at Xp22.3 causing NYS6 (300814).  A locus at Xp11.4-p11.3  contains an as yet unknown mutation responsible for an infantile periodic alternating type: NYS5 (300589). 

Several autosomal dominant forms have been linked to chromosomal regions 6p12 (NYS2; 164100), 7p11 (NYS3, 608345), 13q (NYS4, 193003), 1q31.3-q32.1, and NYS7 (614826).  Autosomal recessive inheritance has been proposed for several pedigrees but adequate documentation is lacking (see 257400).

Pedigree: 
Autosomal dominant
Autosomal recessive
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Congenital nystagmus cannot be cured.  However, several treatments may be beneficial.  Glasses and contact lenses, and, occasionally, extraocular muscle surgery may be helpful.  The latter should be considered especially when patients adopt a consistent head position for best vision.  This avoids long-term secondary changes in neck muscles and many individuals experience an improvement of two or more lines in visual acuity.  Low vision aids should be offered.

References
Article Title: 

Incidence and Types of Pediatric Nystagmus

Nash DL, Diehl NN, Mohney BG. Incidence and Types of Pediatric Nystagmus. Am J Ophthalmol. 2017 Jul 19. pii: S0002-9394(17)30301-X. doi: 10.1016/j.ajo.2017.07.006. [Epub ahead of print].

PubMed ID: 
28734813
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