myopia

Blepharoptosis, Myopia, Ectopia Lentis

Clinical Characteristics
Ocular Features: 

A mother and 2 daughters with ectopia lentis, myopia, and blepharoptosis have been reported.  The axial length of the globes was increased in the mother and one of the daughters while the myopia in the other daughter with ectopia lentis was presumably lens-induced as the equator bisected the visual axis (axial length approximately 25mm).  The upper lid creases were considered to be abnormally high but levator function was good, consistent with levator aponeurosis disinsertion.  Extraocular movements were normal.  

Systemic Features: 

No systemic abnormalities were present.  More specifically, there was no evidence of Ehlers-Danlos (225400) or Marfan syndrome (154700).

Genetics

The presence of similar findings in a mother and 2 daughters suggests autosomal dominant inheritance but no locus has been identified. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Displaced lenses may need to be removed. 

References
Article Title: 

Donnai-Barrow Syndrome

Clinical Characteristics
Ocular Features: 

A number of ocular features have been described in this disorder, including telecanthus, hypertelorism, and iris hypoplasia with marked iris transillumination.  Myopia is commonly present and retinal detachments are a risk.  Several patients had iris colobomas.  Cataracts, small optic nerves, and macular hypoplasia have been reported as well.  The lid fissures usually slant downward. 

Systemic Features: 

The facial dysmorphology, in addition to the periocular malformations, includes a prominent brow or frontal bossing, posterior rotation of the ears, a flat nasal bridge and a short nose.  Sensorineural hearing loss is universal and at least some patients have complete or partial agenesis of the corpus callosum, and an enlarged anterior fontanel.  Diaphragmatic and umbilical hernias often occur together.  Low-molecular-weight proteinuria in the absence of aminoaciduria is a frequent feature.  Developmental delays are often seen but occasional patients have normal intellect.  Rare patients have seizures. 

Genetics

This is a rare autosomal recessive disorder caused by homozygous mutations in the LRP2 (low-density lipoprotein receptor-related protein 2 or megalin) gene located at 2q24-q31.  Some patients have an ocular phenotype resembling the Stickler syndrome (609508).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is focused on specific manifestations such as cataract and retinal detachment surgery. Patients need to be monitored throughout life for retinal disease.  Omphaloceles and diaphragmatic hernias need to be repaired.  Hearing aids may be beneficial. 

References
Article Title: 

Walker-Warburg Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are usually small and contain either retinal dysplasia or a congenital retinal detachment.  Colobomas, PHPV, cataracts, glaucoma, buphthalmos, anterior chamber dysgenesis, optic atrophy, and optic nerve hypoplasia have also been reported. 

Systemic Features: 

Hydrocephalus and congenital muscular dystrophy are the most important systemic features of these syndromes.  A Dandy-Walker malformation is often present.  Type II lissencephaly, cerebellar malformations and severe mental retardation are other features.  More variable signs include macro- or microcephaly, ventricular dilatation, cleft lip and/or palate, and congenital contractures.  WWS has a severe phenotype and death often occurs in the first year of life.  Brain histology shows severely disorganized cytoarchitecture and suggests a neuronal migration disorder. Microtia has been reported in several patients.

Most developmental milestones are delayed or never achieved and death may occur in early childhood. 

Genetics

The MDDGs (muscular dystrophy dystroglycanopathies) comprise a genetically and clinically heterogeneous group of disorders (sometimes called muscle-eye-brain disease) of which the A types are more severe than the B types.  The mutant genes responsible are involved in glycosylation of DAG1 (alpha-dystroglycan). 

Types A1 (MDDGA1; 236670), B1 (MDDGB1; 613155) and C1 (MDDGC1; 609308) result from mutations in a gene known as POMT1 (9p34.1).  The muscular dystrophy in type C1 is of the limb-girdle type LGMD2K.

A2 (MDDGA2; 613150) is caused by mutations in POMT2 (14q24.3).  Mutations in POMT2 may also cause the less severe muscle-eye-brain disease (MEB) type B2 (MDDGB2; 613156), and a similar disease (C2) in which the muscle dystrophy is of the limb-girdle type LGMD2N and eye findings may be absent (MDDGC2; 613158).

Mutations in POMGNT1 (1p34-p33) cause type A3 (MDDGA3; 253280) and type B3 (MDDGB3; 613151).  The muscular dystrophy in B3 is of the limb-girdle type.  POMGNT1 mutations may be associated with congenital glaucoma, retinal dysplasia, and high myopia. Type C3 (MDDGC3; 613157), also with a limb-girdle type of muscular dystrophy (LGMD2O), is caused by mutations in POMGNT1 as well.

FKTN mutations cause type A4 MDDG (MDDGA4; 253800) associated with the Fukuyama type of congenital muscular dystrophy but they can also cause type B4 (MDDGB4; 613152) which does not have mental retardation, and type C4 (MDDGC4; 611588) with seizures and a limb-girdle type (LGMD2M) of muscular dystrophy.

Types A5 (MDDG5A; 613153) and B5 (MDDGB5; 606612) are the result of mutations in the FKRP gene (19q13.3).  Of the two the latter is the less severe and the muscular dystrophy is of the limb-girdle type.  The eyes may be microphthalmic and have retinal pigmentary changes and congenital glaucoma.

Type A6 (MDDGA6; 613154) and B6 (MGGDB6; 608840) are caused by mutations in the LARGE gene (22q12.3).  MDDGA7, or type A7 (614643) results from homozygous or compound heterozygous mutations in the ISPD gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available but early indications are that FKRP gene therapy restores functional glycosylation and improves muscle functions.

References
Article Title: 

Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study

Mercuri E, Messina S, Bruno C, Mora M, Pegoraro E, Comi GP, D'Amico A, Aiello C, Biancheri R, Berardinelli A, Boffi P, Cassandrini D, Laverda A, Moggio M, Morandi L, Moroni I, Pane M, Pezzani R, Pichiecchio A, Pini A, Minetti C, Mongini T, Mottarelli E, Ricci E, Ruggieri A, Saredi S, Scuderi C, Tessa A, Toscano A, Tortorella G, Trevisan CP, Uggetti C, Vasco G, Santorelli FM, Bertini E. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009 May 26;72(21):1802-9.

PubMed ID: 
19299310

Myopia 2, Autosomal Dominant, Nonsyndromal

Clinical Characteristics
Ocular Features: 

Nonsyndromal, high myopia (over 6 D) has been found in multiple multigenerational families.  Most individuals have no other ocular problems but a small percentage develop degenerative changes in the retina, particularly in the macula (Fuchs spot).  A few individuals have posterior staphylomas with significant vitreoretinal changes conferring higher risks of retinal detachments and macular holes.  Vitreous traction is often present.  The macula in such cases is may be thickened and microcystic with areas of frank retinoschisis.  Of course, vitreous degeneration and retinal detachments are well known sequelae of high myopia. 

Systemic Features: 

There are no systemic features by definition. 

Genetics

Refractive errors are continuous traits with a wide range in most populations.  This suggests that many developmental and heritable (and perhaps environmental) components are responsible.  No specific mutation has been identified but a number of 'susceptibility' loci have been mapped.

Myopia 2 has been linked to a susceptibility locus at 18q11.31.

Evidence of heritability in both syndromal and isolated myopia comes from several sources.  For example, high myopia is a common feature in familial collagenopathies such as Marfan syndrome (154700), Kniest dysplasia (156550), and Stickler syndrome (108300). Multigenerational families with isolated myopia have been reported as well and mutations in multiple genes (at least 18) have been associated with these.  Heredibility studies using twin pairs have identified additional mutations (609256).  Further, the prevalence of myopia among children increases in the presence of parental myopia.

The transmission pattern in most families to which susceptibility loci have been linked is autosomal dominant.  However, a susceptibility locus has been mapped to 14q22.1-q24.2 in several families with good evidence for autosomal recessive inheritance (255500).  In addition, two loci on the X chromosome have been linked to presumed X-linked myopia (MYP1 [310460] at Xq28 and MYP13 [300613] at Xq23-q25).  A patient with high myopia has been reported with a mutation in the NYX gene on the X-chromosome.  This patient did not have congenital stationary night blindness of the type CSNB1A (310500) in which NYX is usually mutated.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Correction of the refractive error is primary.  High myopes require periodic evaluation throughout life and prompt surgical intervention for retinal detachments.  In extreme myopia it may be especially prudent for individuals to avoid impact sports. 

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 3

Clinical Characteristics
Ocular Features: 

Achromatopsia 3 is a congenital, nonprogressive form of blindness.  It is sometimes referred to as a rod monochromacy or stationary cone dystrophy.  Symptoms are usually present at birth or shortly thereafter.  Patients have pendular nystagmus, progressive lens opacities, severe photophobia, 'day' blindness, and, of course, color blindness.  High myopia is a feature in some populations.  Vision in daylight is often 20/200 or less but vision in dim light is somewhat better. The central scotoma often leads to eccentric fixation. 

The ERG shows a complete absence of cone function.  Optical coherence tomography has demonstrated a reduction in macular volume and thickness of the central retina, most marked in the foveolar region, presumably due in some way to the absence or dysfunction of cone photoreceptors.  Few histologic studies of adequately preserved retina have been reported but those available suggest dysmorphism of cones in the central macula.  The clinical appearance of the retina is usually normal. 

Systemic Features: 

There are no associated systemic abnormalities. 

Genetics

This is an autosomal recessive form of color blindness caused by mutations in CNGB3 (8q21-q22).  This mutation is found in nearly half of patients with achromatopsia.  It is especially common among Pingelapese islanders of the Pacific Caroline Islands where consanguinity occurs frequently due to the founder effect resulting from a 1775 typhoon.  A progressive cone dystrophy has been found in a few patients with mutations in this gene.

Other achromatopsia mutations are in CNGA3 causing ACHM2 (216900), GNAT2 causing ACHM4 (139340), and PDE6C causing ACHM5 (613093).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available but darkly tinted lenses can alleviate much of the photophobia.  Low vision aids and vocational training should be offered.  Refractive errors should, of course, be corrected and periodic examinations are especially important in children. 

References
Article Title: 

The cone dysfunction syndromes

Michaelides M, Hunt DM, Moore AT. The cone dysfunction syndromes. Br J Ophthalmol. 2004 Feb;88(2):291-7. Review.

PubMed ID: 
14736794

Smith-Magenis Syndrome

Clinical Characteristics
Ocular Features: 

Ocular abnormalities have been found in the majority of patients.  Microcornea, myopia, strabismus and iris dysplasia are the most common.  Rare patients have iris colobomas or correctopia.  The eyes appear deep-set and lid fissures are upward slanting.

Systemic Features: 

The facial features are considered to be distinctive, characterized by a broad, square face, prominent forehead, broad nasal bridge, and midface hypoplasia.  These and other features appear more pronounced with age as in the size of the jaw which is underdeveloped in infancy and eventually becomes prognathic.  Most patients have developmental delays, speech and motor deficits, cognitive impairments and behavioral abnormalities.  Hypotonia, hyporeflexia, failure to thrive, lethargy, and feeding difficulties are common in infants.  Older individuals have REM sleep disturbances with self-destructive behaviors, aggression, inattention, hyperactivity, and impulsivity.  Short stature, hypodontia, brachydactyly, hearing loss, laryngeal anomalies, and peripheral neuropathy are common. Seizures are uncommon.

The behavioral profile of this syndrome can resemble that of autism spectrum disorders although symptoms of compulsivity are more mild.

A related developmental disorder known as Potacki-Lupski syndrome (610883) involving the same locus on chromosome 17 has a similar behavioral profile.  Ocular and systemic malformations may be less severe though.

Genetics

Most patients (90%) with the Smith-Magenis syndrome have interstitial deletions in the short arm of chromosome 17 (17p11.2).  However, it is included here since a few have heterozygous molecular mutations in the RAI1 gene which is located in this region.  While there is considerable phenotypic overlap, individuals with chromosomal deletions have the more severe phenotype as might be expected.  For example, those with RAI1 mutations tend to be obese and are less likely to exhibit short stature, cardiac anomalies, hypotonia, hearing loss and motor delays than seen in patients with a deletion in chromosome 17.  However, the phenotype is highly variable among patients with deletions depending upon the nature and size of the deletion.

The retinoic acid induced 1 gene (RAI1) codes for a transcription factor whose activity is reduced by mutations within it.

Familial cases are rare and reproductive fitness is virtually zero.  If parental chromosomes are normal, the risk for recurrence in sibs is less than 1%.  Males and females are equally affected.

In Potocki-Lupski syndrome (610883) there is duplication of the 17p11.2 microdeletion as the reciprocal recombination product of the SMS deletion.   

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Medical monitoring, psychotropic medications and behavioral therapies are all useful.  Special education and vocational training may be helpful for those less severely affected.

References
Article Title: 

Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and

Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM,
Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C,
Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski
JR. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and
delineation of a dosage-sensitive critical interval that can convey an autism
phenotype. Am J Hum Genet. 2007 Apr;80(4):633-49.

PubMed ID: 
17357070

Homocystinuria, Beta-Synthase Deficiency

Clinical Characteristics
Ocular Features: 

More than half of patients have ectopia lentis by the age of 10 years and the dislocation is progressive.  Ectopia lentis occurs in 90% of patients and 94% of these are noted by the age of 20 years.  The lenses seem to be more mobile than those in Marfan syndrome with a significantly increased risk of lens migration into the anterior chamber (19%) or complete dislocation into the posterior chamber (14%).   Lens surgery is required in homocystinuria about 7 years earlier than in Marfan syndrome with 62% of procedures necessitated by pupillary block glaucoma or displacement into the anterior chamber.  Whereas nearly 70% of lenses dislocate superiorly in Marfan syndrome, only 9% of homocystinuria lenses do so.

Other ocular features include optic atrophy (23%), iris atrophy (21%), anterior staphylomas (13%) and corneal opacities (9%).  Retinal detachments occur in 5-10%.  The majority of patients both pre- and postoperatively have vision of 20/50 or worse.

Systemic Features: 

Arachnodactyly and tall stature in some patients may suggest Marfan syndrome.  Mental deficiencies or behavioral problems are present in a majority of patients (50-60%) with mental functioning higher in the subset of patients who are B6-responsive.  Thromboembolic events (strokes, myocardial infarctions) are a significant risk at any age, especially so after age 20 years, and this is responsible for considerable morbidity and mortality.  The risk is especially high following general anesthesia unless hydration is strictly controlled.  Osteoporosis and seizures are common.  Hypopigmentation is often present but darkening of hair has been noted following pyridoxine treatment.  Serum homocysteine is generally elevated and the urine contains elevated levels of methionine.

Genetics

Classic homocystinuria is an autosomal recessive disorder that results from mutations in the CBS (21q22.3) gene encoding cystathionine beta-synthase.  It is the second most common error of amino acid metabolism.  Numerous mutations have been identified but among the most common ones are I278T which causes a pyridoxine-responsive disorder, and the G3307S mutation which leads to a variant that is not responsive to pyridoxine treatment.

For another more aggressive form of homocystinuria caused by mutations in MTHFR (1p36.3) see Homosystinuria, MTHER Deficiency (236250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Patients with this disorder form two groups: those who respond to pyridoxine (vitamin B6) and those who do not.  Those who do not respond to B6 tend to have more severe disease.  Methionine restriction administered neonatally has been reported to prevent mental retardation and reduce the rate of lens dislocation.  Neonates should be treated with B6 therapy, protein and methionine restriction, betaine, and folate with vitamin B12 supplementation.  Surgical removal of lenses may be required but the rate of vitreous loss is high.

References
Article Title: 

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