nystagmus

Spastic Ataxia 7, with Miosis

Clinical Characteristics
Ocular Features: 

Several large pedigrees have been reported in which both males and females had congenital miosis and decreased pupillary light responses.  The pupils are about 2 mm in size and have been described as 'fixed' since they do not dilate in low light or constrict in bright light.  They also do not respond well to mydriatics.  Several individuals also had nystagmus and dysconjugate eye movements.

Optic atrophy is not a consistent feature although several in the original reported family were reported to have this feature which is often found in other spastic ataxia disorders, such as Friedreich's ataxia (229300).

Systemic Features: 

Ataxia in gait and limb motion with pyramidal signs is part of this disorder.  Deep tendon reflexes are increased and plantar responses are often extensor in direction.  Both pyramidal signs and the ataxia progress little.  Affected individuals begin walking late and often have slurred speech.  The IQ's in one family were measured to be less than 90.  CT scans have not revealed cerebellar atrophy.

Genetics

This condition is likely inherited in an autosomal dominant pattern based on one pedigree with 21 members in 4 generations and another with an affected mother and 3 of 5 affected children.  Nothing is known about the locus responsible.

Optic atrophy is also found in autosomal recessive SPAX4 (613672) and in an ill-defined autosomal recessive form of spastic ataxia with mental retardation (270500).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for this disorder.

References
Article Title: 

Cornelia de Lange Syndrome

Clinical Characteristics
Ocular Features: 

Many patients have few ocular findings beyond the usual synophyrs, a highly arched brow with hypertrichosis, and long eyelashes.  Synophrys is often prominent.  However, some also have significant ptosis, nystagmus, and high refractive errors.  Optic pallor and a poor macular reflex have also been reported.

Systemic Features: 

The facial features may be distinctive with low anterior hairline, anteverted nares, maxillary prognathism, long philtrum, crescent-shaped mouth and, of course, the bushy eyebrows and long lashes (in 98%).  Mental and growth retardation are common while many patients have features of the autism spectrum and tend to avoid social interactions.  The lips appear thin, the mouth is crescent-shaped, the head is often small, the teeth are widely spaced, and the ears are low-set.  The hands are often deformed with a proximally positioned thumb and metacarpophalangeal deformities.  It is stated that the middle phalanx of the index finger is always hypoplastic.  Other limb abnormalities of both upper (95%) and lower extremities are common.  Urinary tract abnormalities have been found in 41% of patients.  Middle ear effusions often lead to conductive hearing loss but 80% of patients have a sensorineural hearing deficit.

Genetics

This disorder is caused by mutations in genes encoding components of the cohesion complex.  Most cases occur sporadically but numerous familial cases suggest autosomal dominant inheritance. However, since at least three genes code for components of the cohesion complex including one located on the X-chromosome (610759), familial cases reported earlier without genotyping have created some confusion.  Hence, even autosomal recessive inheritance has been suggested in some families.  Genetic counseling should be family-specific based on the genotype and family pattern.

About 50% of cases result from mutations in the NIPBL gene (122470; 5p13.1) but less than 1% have an affected parent and the recurrence risk for sibs is similar.  The X-linked form of CDLS (300590; Xp11.22-p11.21) is caused by a mutation in the SMC1A gene, and a mild form (610759) results from mutations in the SMC3 gene (10q25).  Mutations in RAD21 (8q24) have been found in patients with milder disease and atypical presentations (614701).

A CDLS phenotype can also result from a specific duplication of a 3q 26-27 band.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No genetic treatment is available.

References
Article Title: 

Chédiak-Higashi Syndrome

Clinical Characteristics
Ocular Features: 

The ocular hypopigmentation and visual function deficits in Chediak-Higashi syndrome resembles that of other types of albinism.  The iris has transillumination defects and the retina is hypopigmented.  Patients are photophobic and often have nystagmus.  Due to the early mortality of many patients, vision is difficult to measure, but is said to range from normal to near normal.  Hair bulb incubations studies show normal pigmentation.

A  subset of patients with later onset of disease has been reported to have optic atrophy, thinning of the nerve fiber layer, and a central scotoma.

Systemic Features: 

This is a form of albinism with other systemic features such as adenopathy, hepatosplenomegaly, neutropenia, and susceptibility to infection (especially gram positive organisms).  The hypopigmentation is evident at birth but may be patchy.  The hair has been described as having a blue-green metallic sheen.  It may also be sparse.  Patients have an increased risk of leukemia and lymphoma-like disease.  Peripheral sensory-motor neuropathy and ataxia are common in older individuals.  Thrombocytopenia can lead to easy bruising and extensive bleeding.  Neutrophils are often few in number and deficient in chemotactic and bacterial activity.  Pyoderma and peridontitis can be severe.  Survival without treatment is between 3 and 4 years but those who survive eventually develop lymphohistiocytic infiltration of major organs, bone marrow and peripheral nerves as young adults.

Giant peroxidase-positive inclusions in white blood cells are diagnostic.

Genetics

This is an autosomal recessive disorder caused by mutations in the LYST gene (1q42.1-q42.2) causing defects in vesicle trafficking.

Hermansky-Pudlak syndrome (214500) is another form of hypopigmentation with serious systemic manifestations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Bone marrow transplantation can prolong life but neurologic symptoms often develop in those who survive.  Low-vision aids can be helpful.  Infections, of course, should be promptly and vigorously treated.

References
Article Title: 

Optic neuropathy in late-onset neurodegenerative Chédiak-Higashi syndrome

Desai N, Weisfeld-Adams JD, Brodie SE, Cho C, Curcio CA, Lublin F, Rucker JC. Optic neuropathy in late-onset neurodegenerative Chediak-Higashi syndrome. Br J Ophthalmol. 2015 Aug 25. pii: bjophthalmol-2015-307012. doi: 10.1136/bjophthalmol-2015-307012. [Epub ahead of print].

PubMed ID: 
26307451

Chédiak-Higashi syndrome

Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol. 2008 Jan;15(1):22-9. Review. PubMed PMID: 18043242.

PubMed ID: 
18043242

Incontinentia Pigmenti

Clinical Characteristics
Ocular Features: 

This is primarily a disorder of skin, teeth, hair, and the central nervous system but 35% of patients have important ocular features.  The iris is variably atrophic and has pigmentary anomalies often with posterior synechiae.  Nystagmus, strabismus, and limited vision are often present.  The majority (up to 90%) of individuals have significant retinal disease.  The retinal vascular pattern is anomalous with tortuosity in some areas and absence of vessels in others.  Preretinal fibrosis and retinal detachments may suggest the presence of a retinoblastoma.  Cataracts are common in patients who have a retinal detachment and some patients have microphthalmia. The retinal pigment epithelium is often abnormal with various-sized patches of sharply demarcated depigmentation.  Cases with uveitis, papillitis and chorioretinitis have been observed and it has been suggested that the observed retinal and choroidal changes result from prior inflammatory disease, perhaps even occurring in utero. There is a great deal of asymmetry in the clinical findings in the two eyes.

Systemic Features: 

Skin changes consisting of erythematous eruptions in a linear pattern are often present at birth and this may be followed by a verrucous stage.  The acute, early findings of inflammatory disease eventually subside, ultimately resulting in pigmentary changes that appear in a 'marbled pattern' in young adults.  Hypodontia and anodontia may be present.  Alopecia and CNS abnormalities are found in nearly half of patients.  Skeletal and structural deformities are common in patients with severe neurological deficits.  The only sign of this disorder in adult women may be a whorled pattern of scarring alopecia.

As many as 30% of patients have neurological features which may be present in the neonatal period.  Seizures of various types occur in 30% of patients.  MRI findings include periventricular and subcortical white matter changes, as well as corpus callosum hypoplasia, cerebral atrophy, and cerebellar hypoplasia.

 

Genetics

The majority of evidence suggests that this is an X-linked dominant disorder with lethality in males although sporadic cases occur.  The mutation occurs as a genomic rearrangement of the IKK-gamma gene, also known as NEMO (IKBKG) located at Xq28.  There is evidence from skin cultures that cells with the mutant X chromosome inactivated are preferentially viable.  It has been proposed that cells with the mutant bearing X chromosome as the active one are gradually replaced by those in which the normal X chromosome is active accounting for the post-natal course of the skin disease.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

No treatment for the generalized disorder is available although ocular surgery might be beneficial in rare cases with cataracts and detachments.

References
Article Title: 

Baller-Gerold Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features are a rather minor part of this syndrome and are found in less than a third of patients.  These primarily involve lids and adnexae with telecanthus, downslanting lid fissures, and epicanthal folds.  Some individuals have nystagmus while strabismus, blue sclerae, and ectropion have also been reported.

Systemic Features: 

The cardinal features of this syndrome are craniosynostosis and radial defects.  However, a large number of variable defects such as imperforate or anteriorly placed anus, rectovaginal fistula, absent thumbs, polydactyly, and mental retardation may also be present.  The radius may be completely absent or abnormally formed and occasionally the ulnar bone is involved as well.  Some patients have a conductive hearing loss.

Genetics

This syndrome is caused by a mutation in the RECQL4 gene at 8q24.3 and seems to be an autosomal recessive disorder.  Its syndromal status as a unique syndrome is in some doubt because of considerable phenotypic overlap with other entities such as Roberts (268300) and Saethre-Chotzen (101400) syndromes.  The latter however is caused by a mutation in the TWIST1 gene and the former by mutations in the ESCO2 gene.

The same gene is mutated in Rothmund-Thomson syndrome (268400) suggesting allelism of the two disorders.  The phenotype is vastly different in the two disorders however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Carpenter Syndrome

Clinical Characteristics
Ocular Features: 

A variety of ocular anomalies have been reported in Carpenter syndrome with none being constant or characteristic.  The inner canthi are often spaced widely apart and many have epicanthal folds and a flat nasal bridge.  Other reported abnormalities are nystagmus, foveal hypoplasia, corneal malformations including microcornea, corneal opacity, and mild optic atrophy and features of pseudopapilledema.

Systemic Features: 

Premature synostosis involves numerous cranial sutures with the sagittal suture commonly involved causing acrocephaly (tower skull).  Asymmetry of the skull and a 'cloverleaf' deformity are often present.  The polydactyly is preaxial and some degree of syndactyly is common especially in the toes.  The digits are often short and may be missing phalanges.  Some patients are short in stature.  Structural brain defects may be widespread including atrophy of the cortex and cerebellar vermis.  Septal defects in the heart are found in about one-third of patients.  The ears can be low-set and preauricular pits may be seen.  Some but not all patients have obesity and a degree of mental retardation.

Genetics

This is an autosomal recessive syndrome caused by a mutation in the RAB23 gene (6p12.1-q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment of the ocular defects is necessary in most cases. Craniectomy may be required in cases with severe synostosis.

References
Article Title: 

Carpenter syndrome

Hidestrand P, Vasconez H, Cottrill C. Carpenter syndrome. J Craniofac Surg. 2009 Jan;20(1):254-6.

PubMed ID: 
19165041

RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity

Jenkins D, Seelow D, Jehee FS, Perlyn CA, Alonso LG, Bueno DF, Donnai D, Josifova D, Mathijssen IM, Morton JE, Orstavik KH, Sweeney E, Wall SA, Marsh JL, Nurnberg P, Passos-Bueno MR, Wilkie AO. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet. 2007 Jun;80(6):1162-70. Erratum in: Am J Hum Genet. 2007 Nov;81(5):1114. Josifiova, Dragana [corrected to Josifova, Dragana].

PubMed ID: 
17503333

Albinism, Ocular Type 1

Clinical Characteristics
Ocular Features: 

Signs in ocular albinism include hypopigmentation of the fundus with clearly visible choroidal vessels, foveal hypoplasia, and hypopigmentation of the iris. Strabismus, nystagmus, photophobia, absent stereoacuity and high refractive errors including hypermetropia are other common features.  Vision may be near normal but usually worse, in the range of 20/100 to 20/300.  In at least some patients with ocular albinism, concentric macular rings have been identified using infrared reflectance images.

In ocular albinism there is a nearly complete crossing of nerve fibers in the optic chiasm as well as a decreased number of photoreceptors.  MRI imaging of the optic chiasm in humans with albinism reveals it to be smaller with a wider angle between optic tracts, reflecting the atypical crossing of nerve fibers.

This is an X-linked recessive disorder and affects mainly men. In 80% of female carriers a mosaic of pigmentary changes can be observed in the fundus, especially in the periphery as a result of lyonization.  A few female heterozygotes have ocular changes of albinism including nystagmus and reduced visual acuity, likely as a result of unequal X-chromosome inactivation.  Perhaps three-quarters of carrier females have transillumination defects in the iris.

Hearing loss is often associated with pigmentation disorders and families with X-linked ocular albinism have been reported with a late onset sensorineural deafness (300650).  The ocular findings are typical but deafness is not significant until late midlife.

Systemic Features: 

In ocular albinism, pigmentation is normal except in the eye.  Hearing loss has been reported in a single family but this may be a unique disorder since the genotype was not determined.

Male infertility has been reported in some patients with OCA1 and late-onset sensorineural hearing loss which has been hypothesized ro be part of a contiguous gene deletion syndrome involving GPR143, TBL1X and posssibly SHROOM2 genes.

Genetics

Ocular albinism (OA1) is a recessive X-linked disorder, caused by mutations in the GPR143 gene, located at Xp22.3.  The protein product, a G protein-coupled receptor, is localized on the membrane of melanosomes in pigmented cells in the eye.  The same gene is mutated in congenital nystagmus 6 (300814).  Ocular albinism with late onset sensorineural deafness (300650) results from mutations in the Xp22.3 region as well and may or may not be the same condition.  In some individuals the contiguous genes TBL1X and SHROOM2 may also have mutations (usually microdeletions).

It has been reported that mutations in GNA13 (17q24.1), activated by OA1, can also result in the ocular albinism phenotype.

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

Treatment for the ocular symptoms is targeted toward specific problems. Refractive errors are treated with corrective glasses with tinted lenses recommended for the photophobia. Low vision aids and special education may be required.

References
Article Title: 

Behr Early Onset Optic Atrophy Syndromes

Clinical Characteristics
Ocular Features: 

Optic atrophy is the earliest sign in Behr syndrome and may be evident in early childhood.  Nystagmus is a variable feature.  Acuity in the first decade is in the 20/70 to 20/100 range with little worsening in patients followed for a decade or more even though the disc pallor may increase with loss of papillary vasculature.  ERGs are normal but VEPs are usually abnormal.

Systemic Features: 

The nosology of infantile optic atrophy is unclear.   There is no doubt that some familial cases with likely autosomal recessive inheritance lacked (or were not tested for) urinary metabolites considered diagnostic for an optic atrophy disorder with 3-methylglutaconate aciduria (258501) and labeled methylglutaconic aciduria type III (and sometimes Costeff optic atrophy syndrome).  Excretion of 3-methylglutaric acid may also be increased.  But it is also possible that another form of infantile optic atrophy without aminoaciduria also exists.  Early onset (early childhood) optic atrophy, with later (second decade) spasticity, ataxia, extrapyramidal signs and cognitive defects to some degree are common to both.  Dementia, posterior column signs and peripheral neuropathy are more variable clinical signs.  Nerve biopsies and postmortem studies show widespread disease with evidence of chronic neuropathy, neuronal loss, and gliosis.  In Behr's report, the neurologic symptoms remained static after a period of progression.   Others have reported progression with the majority of patients severely handicapped by the third decade of life.

Genetics

Sibs born to consanguineous parents suggest autosomal recessive inheritance in both Behr syndrome with ataxia and in 3-methylglutaconic aciduria, type III.  The latter is most commonly found among Iraqi Jews and is the result of a mutation in the OPA3 gene (19q13.2-q13.3).  The genetic basis for simple Behr infantile optic atrophy is unclear and it is likely that multiple unique entities exist.  This disorder is allelic to an autosomal dominant disorder called Optic Atrophy 3 and Cataracts (165300) but the uniqueness of the latter entity is uncertain.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known

References
Article Title: 

Aniridia 1

Clinical Characteristics
Ocular Features: 

Aniridia is the name of both a disorder and a group of disorders.  This because aniridia is both an isolated ocular disease and a feature of several malformation syndromes.  Absence of the iris was first reported in the early 19th century.  The hallmark of the disease is bilateral iris hypoplasia which may consist of minimal loss of iris tissue with simple radial clefts, colobomas, pseudopolycoria, and correctopia, to nearly complete absence.  Goniosocopy may be required to visualize tags of iris root when no iris is visible externally.  Glaucoma is frequently present (~67%) and often difficult to treat.  It is responsible for blindness in a significant number of patients.  About 15% of patients are diagnosed with glaucoma in each decade of life but this rises to 35% among individuals 40-49 years of age.  Hypoplasia and dysplasia of the fovea are likely responsible for the poor vision in many individuals.  Nystagmus is frequently present.  The ciliary body may also be hypoplastic. 

Visual acuity varies widely.  In many families it is less than 20/60 in all members and the majority have less than 20/200.  Photophobia can be incapacitating.  Posterior segment OCT changes suggest that outer retinal damage suggestive of a phototoxic retinopathy may also be a factor in the reduced acuity.  Cataracts (congenital in >75%), ectopia lentis (bilateral in >26%), optic nerve hypoplasia, variable degrees of corneal clouding with or without a vascularized pannus, and dysgenesis of the anterior chamber angle are frequently present. 

Increased corneal thickness (>600 microns) has been found in some series and should be considered when IOP measurements are made.  In early stages of the disease, focal opacities are present in the basal epithelium, associated with sub-basal nerves.  Dendritic cells can infiltrate the central epithelium and normal limbal palisade architecture is absent. 

Meibomian gland anomalies also contribute to the corneal disease.  The glands may be decreased in number and smaller in size contributing to deficiencies of the tear film and unstable surface wetting.

Systemic Features: 

In addition to 'pure' aniridia in which no systemic features are found, at least six disorders have been reported in which systemic anomalies do occur.  Three of these have associated renal anomalies, including Wilms tumor with other genitourinary anomalies and mental retardation, sometimes called WAGR (194072) syndrome, another (612469) with similar features plus obesity sometime called WAGRO (612469) syndrome reported in isolated patients, and yet another with partial aniridia (206750) and unilateral renal agenesis and psychomotor retardation reported in a single family.  Aniridia with dysplastic or absent patella (106220) has been reported in a single three generation family.  Cerebellar ataxia and mental retardation with motor deficits (Gillespie syndrome; 206700) have been found in other families with anirdia.  Another 3 generation family has been reported in which aniridia, microcornea and spontaneously resorbed cataracts occured (106230).

About one-third of patients with aniridia also have Wilms tumor and many have some cognitive deficits.

Genetics

The majority of cases have a mutation in the paired box gene (PAX6) complex, or at least include this locus when chromosomal aberrations such as deletions are present in the region (11p13).  This complex (containing at least 9 genes) is multifunctional and important to the tissue regulation of numerous developmental genes.   PAX6 mutations, encoding a highly conserved transcription regulator, generally cause hypoplasia of the iris and foveal hypoplasia but are also important in CNS development.  It has been suggested that PAX6 gene dysfunction may be the only gene defect associated with aniridia.  More than 300 specific mutations, most causing premature truncation of the polypeptide, have been identified.  

AN1 results from mutations in the PAX6 gene.  Two additional forms of aniridia have been reported in which functional alterations in genes that modulate the expression of PAX6 are responsible: AN2 (617141) with mutations in ELP4 and AN3 (617142) with mutations in TRIM44.  Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.

Associated abnormalities may be due to a second mutation in the WT1 gene in WAGR (194072) syndrome, a deletion syndrome involving both WT1 and PAX6 genes at 11p13.  The WAGRO syndrome (612469) is caused by a contiguous deletion in chromosome 11 (11p12-p13) involving three genes: WT1, PAX6, and BDNF.  All types are likely inherited as autosomal dominant disorders although nearly one-third of cases occur sporadically.

Mutations in PAX6 associated with aniridia can cause other anterior chamber malformations such as Peters anomaly (604229).

Gillespie syndrome (206700 ) is an allelic disorder with neurological abnormalities including cerebellar ataxia and mental retardation.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at the associated threats to vision such as glaucoma, corneal opacities, and cataracts.  Glaucoma is the most serious threat and is the most difficult to treat. The best results have been reported with glaucoma drainage devices.  All patients should have eye examinations at appropriate intervals throughout life, focused on glaucoma screening.  It is well to keep in mind that foveal maldevelopment often precludes significant improvement in acuity and heroic measures must be carefully evaluated.  Specifically, corneal transplants and glaucoma control measures frequently fail.

Low vision aids are often helpful.  Tinted lenses can minimize photophobia.  Occupational and vocational training should be considered for older individuals.  Surface wetting of the cornea should be periodically evaluated and appropriate topical lubrication used as needed. 

Young children with aniridia should have periodic examinations with renal imaging as recommended by a urologist.

In mice, postnatal topical ocular application of ataluren-based eyedrop formulations can reverse malformations caused by PAX6 mutations.

References
Article Title: 

Familial aniridia with preserved

Elsas FJ, Maumenee IH, Kenyon KR, Yoder F. Familial aniridia with preserved ocular function. Am J Ophthalmol. 1977 May;83(5):718-24.

PubMed ID: 
868970

Aland Island Eye Disease

Clinical Characteristics
Ocular Features: 

This is an X-linked disorder in which males have a variety of ocular defects.  The fundus is hypopigmented and the fovea is incompletely developed.  The hypopigmentation is most pronounced in the posterior pole and peripapillary region.  Variable degrees of iris transillumination have also been noted.  Progressive axial myopia, nystagmus, astigmatism, defective night vision, and a protan color vision defect are additional cardinal features.  Females may be mildly affected with subtle nystagmus and color vision defects.  It is sometimes mislabeled as X-linked albinism (OA1, #300500) but differs importantly from that disorder by the lack of misrouting of optic nerve axons.  The eponymic label 'Forsius-Eriksson type ocular albinism' further adds to the confusion with ocular albinism. 

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an X-linked disorder resulting from a mutation in the CACNA1F gene located at Xp11.23.  Molecular DNA studies suggest that there may be some heterogeneity in the causative mutations but in the original family reported by Forsius and Eriksson, a 425-bp deletion in the CACNA1F gene has been found to segregate as expected in the phenotypes.  The highly variable and subtle nature of clinical manifestations in females limits their usefulness in determination of carrier status and genotyping is necessary.

The CSNB2A type of congenital stationary night blindness (300071) is caused by mutations in the same gene suggesting allelism of the two disorders.  Aland Island eye disease shares some clinical features such as night blindness and occasionally mild color vision defects but differs in the presence of progressive myopia and an abnormal fovea. 

CORDX3 (300476), a cone-rod dystrophy, is also allelic.

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

No treatment is available except for correction of the myopia.

References
Article Title: 

A novel CACNA1F gene mutation causes Aland Island eye disease

Jalkanen R, Bech-Hansen NT, Tobias R, Sankila EM, M?SSntyj?SSrvi M, Forsius H, de la Chapelle A, Alitalo T. A novel CACNA1F gene mutation causes Aland Island eye disease. Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2498-502. PubMed PMID:17525176.

PubMed ID: 
17525176

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