astigmatism

Alkaptonuria

Clinical Characteristics
Ocular Features: 

Ocular signs of this disease are present in two out of three patients.  Black or bluish pigmented patches may be noted in the sclerae by the fourth decade. The pigmentation is most evident just anterior to the insertion of the medial and lateral rectus muscles.  It is claimed that brown pigment spots resembling 'oil drops' near the opaque portion of the limbus are diagnostic but they are often not present until the 4th or 5th decades.  Nevertheless, these ocular signs on average precede systemic signs by about 15 years and are therefore diagnostically useful.  The pigmentation has no impact on vision. Hyperpigmentation of the anterior chamber angle with elevated intraocular pressure has been reported.  An increased incidence of central vein occlusion has been suggested.  Progressive astigmatism is sometimes seen.  Staining of the tarsal plates may be seen in the eyelids.

Systemic Features: 

Ochronosis (dark pigmentation in connective tissue) as the result of homogentisic acid (HGA) accumulation is a useful sign but does not appear until the 4th decade.  As a result the joint cartilage becomes fragile leading to disabling and chronic symptoms of arthritis especially in the spine and large joints.  Symptoms usually begin in the third or fourth decade and the degeneration of the ochronotic intervertebral disks may result in significant loss of height.  Back pain, kyphosis, and decreased lumbar flexion are common.  Usually smaller joints such as those of the digits are not affected sufficiently to cause symptoms.

Tendons, ligaments, and other fibrous tissue such as sclerae and heart valves are all susceptible to degenerative changes.  The discoloration in skin hue can also be seen in the axillae, nail beds, pinnae, forehead, tympanic membranes, genital areas, and buccal mucosa.  Clothing may become stained from discolored perspiration.

HGA in the urine oxidizes and turns dark and parents may note staining of diapers in the newborn period.  The urine also becomes alkaline.  Plasma levels of HGA are also elevated.  Urolithiasis may occur.

Genetics

This metabolic disease is among the first inborn errors of metabolism described.  Virchow had early described the yellowish discoloration of connective tissue seen under the microscope.  William Bateson at the beginning of the 20th century suggested the heritability of this condition to the British physician Sir Archibald Garrod who then described this syndrome in 1902 as the first human disease whose transmission pattern conformed to mendelian autosomal recessive inheritance based on his understanding of Mendel's laws.

Homozygosity of mutations in the HGD gene (3q13.33) coding for homogentisate 1,2-dioxygenase is responsible for the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Nitisinone reduces the production of HGA and can lower urinary levels up to 95% but may lead to elevated plasma tyrosine that rarely results in the deposition of corneal crystals.  Long-term benefits of nitisinone remain unknown. Others have tried dietary reduction of tyrosine and phenylalanine with reduction in HGA levels but the long term impact on the rate of tissue degradation remains unknown.    

Additional treatment is directed at specific damaged sites.  Calcified valves (often aortic) may need to be replaced.  Large joints such as hips, shoulders, and knees often require replacement for pain relief.  Stones in the urinary tract may need to be removed.  Ophthalmologists should keep such patients under observation for progressive astigmatism and the risk of elevated intraocular pressure.

It may be prudent to avoid contact sports and minimize heavy weight lifting to limit trauma to joint cartilage.

References
Article Title: 

Natural history of alkaptonuria

Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA. Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26;347(26):2111-21.

PubMed ID: 
12501223

The molecular basis of alkaptonuria

Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, Renedo M, Fernandez-Ruiz E, Penalva MA, Rodriguez de Cordoba S. The molecular basis of alkaptonuria. Nat Genet. 1996 Sep;14(1):19-24.

PubMed ID: 
8782815

Cornea, Ring Dermoid

Clinical Characteristics
Ocular Features: 

Dermoids in this condition are found at the limbus extending onto the cornea anteriorly and into the conjunctiva posteriorly.  They may be unilateral or bilateral and some contain functional hair follicles.  They are present at birth and appear as raised yellow-white tissue which can be segmental or extend for the full limbal circumference.  Some present as a dark ring around the cornea.  The apophyses can be elevated 2-3mm and extend for 3-5mm laterally.  Corneal changes, primary or secondary, lead to progressive vision loss in older individuals. Corneal distortion can result in significant astigmatism.  Some patients have glaucoma and congenital cataracts.

Histological studies have not been reported.

Systemic Features: 

No systemic disease is part of this condition.

Genetics

Two families, one Peruvian and one Chinese, have been reported with autosomal dominant patterns of transmission.  A G185A substitution in the PITX2 gene (4q25) cosegregated with the ocular disease in the Chinese family.

PITX2 encodes a transcription factor important to the development of multiple organs including the eye.  Mutations in this gene have also been found in patients with Peters anomaly (604229), a form of iris hypoplasia with goniodysgenesis (IRID2) (137600), and in Type 1 Axenfeld-Rieger syndrome (180500).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical excision may be necessary in patients with extensive disease.  Patients need to be monitored for cataracts, amblyopia, and glaucoma.

References
Article Title: 

Fibrosis of Extraocular Muscles, CFEOM1

Clinical Characteristics
Ocular Features: 

Hereditary CFEOM is a congenital, nonprogressive condition.  The eyes are usually fixed in the infraducted position about 20-30 degrees below the primary position.  Horizontal movement is absent or severely restricted.  Blepharoptosis is almost always present and patients exhibit a marked chin-up position of gaze.  Binocularity is usually absent.  Some patients have large amounts of astigmatism.  Amblyopia has been reported to occur on a refractive or strabismic basis.  However, careful examination of the optic nerve may reveal anomalies such as increased cupping, asymmetric cupping and hypoplasia and could be responsible for the reduced vision in some patients.

Neuropathologic studies in rare patients have shown defects in brainstem neural development including in one case absence of the superior division of the oculomotor nerve.  Fibrosis of extraocular muscles and Tenon's capsule as well as adhesions to the globe and between muscles have been described.   Anomalous insertions of EOMs may also occur.  An MRI can reveal atrophy of the levator palpebrae and the superior rectus muscles as well as absence or hypoplasia of the oculomotor and sometimes abducens nerves.  It is now considered that CFEOM disorders result from primary neuronal disease resulting in secondary myopathy. 

Systemic Features: 

Late onset gait abnormalities associated with MRI documented vermis atrophy have been reported in a single autosomal dominant pedigree.  The diagnosis of CFEOM1 was confirmed with molecular studies but only two older individuals aged 79 and 53 years had the cerebellar atrophy while a 33 year old in the same family had only CFEOM with no gait difficulties and no neuroimaging abnormalities.

Genetics

CFEOM1 is an autosomal dominant disorder caused by mutations in the KIF21A gene located at 12q12.  This is considered the classic form of congenital, restrictive strabismus but other types such as CFEOM2 (602078) and CFEOM3 (600638, 609384) have also been reported.  CFEOM3 is a clinically heterogeneous autosomal dominant condition and the label is usually applied to individuals who do not meet the criteria for the other two types.  A rare subtype (CFEOM3B) is also due to mutations in the KIF21A gene.  CFEOM3A (600638) is caused by mutations in the TUBB3 gene (16q24) while CFEOM3C (609384) maps to 13q.

The CFEOM2 (602078) phenotype is due to mutations in the PHOX2A (ARIX) gene and inherited in an autosomal recessive pattern.

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM3C (609384), CFEOM5 (616219), and CFEOM with synergistic divergence (609612).  See also Tukel CFEOM syndrome (609428).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Normal ocular movements cannot be restored but large recessions of the inferior recti followed by frontalis suspension of the upper eyelids can improve severe ptosis and the compensatory chin-up gaze. Corneal lubrication must be maintained.  Refractive errors and amblyopia should be corrected.  

References
Article Title: 

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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