autosomal recessive

Tangier Disease

Clinical Characteristics
Ocular Features: 

This disorder of lipoprotein metabolism is associated in many cases with corneal infiltrates, cicatricial ectropion, poor lid closure, and exposure keratopathy.  The corneal clouding alone generally cause little reduction of acuity but those with poor lid function and exposure keratopathy may have severe vision loss.  There may be weakness in the periorbital and lid muscles.  The corneal infiltration occurs late in life but is progressive with older individuals having the greatest visual impairment.  The corneal infiltrates are described as a “dot-like haze”, more prominent centrally and located in the stroma.  On electron microscopy, deposits in the conjunctiva are described as birefringent lipid particles located in pericytes and fibrocytes.  Lipid deposition occurs throughout the body including the conjunctiva.  Corneal hypesthesia has been reported.

In a series of 13 patients, ectropion and corneal scarring were reported in 3 and corneal infiltrates in 9.  Four had orbicular muscle weakness.  The latter together with corneal hypesthesia may be the earliest ocular signs of Tangier disease and should suggest the diagnosis even before the corneal clouding occurs.

Systemic Features: 

Patients with Tangier disease have significant enlargement of the liver, spleen and lymph nodes.  The tonsils are also frequently enlarged and have a characteristic yellow-orange  coloration.  The enlargement of these organs is due to lipid infiltration.  Plasma levels of cholesterol and HDL are characteristically slightly low while triglycerides are mildly elevated.  Peripheral neuropathy and muscle atrophy can be debilitating.  Severe coronary artery disease is common with onset sometime in the 5th decade.

Genetics

Tangier disease is an autosomal recessive disorder resulting from mutations in the ATP-binding cassette-1 gene ABCA1 (9p31.1) located in exon 22.  Parental consanguinity is common.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder beyond local organ treatment as indicated.
 

References
Article Title: 

Ocular complications of Tangier disease

Pressly, T. A.; Scott, W. J.; Ide, C. H.; Winkler, A.; Reams, G. P. : Ocular complications of Tangier disease. Am. J. Med. 83: 991-994, 1987.

PubMed ID: 
3314502

Neuhauser Syndrome

Clinical Characteristics
Ocular Features: 

This rare disorder is characterized by profound mental retardation and megalocornea together with nonspecific facial features including epicanthal folds, broad nasal root, frontal bossing and antimongoloid lid slanting.

Systemic Features: 

Hypotonia and marked psychomotor retardation are the most prominent systemic features.   Short stature, hypercholesterolemia, seizures and hypothyroidism have also been reported.

Genetics

No specific mutation has been found.  Most cases occur sporadically.  The mode of inheritance is presumed to be autosomal recessive on the basis of parental consanquinity found in occasional parents with multiple affected offspring.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.
 

References
Article Title: 

Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhäuser Syndrome and Central Corneal Thickness

Davidson AE, Cheong SS, Hysi PG, Venturini C, Plagnol V, Ruddle JB, Ali H, Carnt N, Gardner JC, Hassan H, Gade E, Kearns L, Jelsig AM, Restori M, Webb TR, Laws D, Cosgrove M, Hertz JM, Russell-Eggitt I, Pilz DT, Hammond CJ, Tuft SJ, Hardcastle AJ. Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhauser Syndrome and Central Corneal Thickness. PLoS One. 2014 Aug 5.

PubMed ID: 
25093588

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

Cornea Plana

Clinical Characteristics
Ocular Features: 

Enlargement of the cornea with flattening is characteristic of cornea plana although corneal diameters vary widely.  Corneal thinning may be present.  The mean corneal refraction value at the horizontal median has been measured at 37.8 D for the dominant form (CNA 1) of the disease, compared with 29.9 D for the recessive form (CNA 2) and 43.4 D for controls accounting for the hyperopia found among many patients.  The limbal margin may be widened with blurring of the corneolimbal junction.  Recessive cases can often be distinguished from the dominant ones by the presence of a central 5 mm area of thickening and clouding.  Recessively inherited cases are also more likely to have anterior synechiae and other iris anomalies.  Early onset arcus has been reported.

Vision in mild cases may be as good as 20/25 or 20/30 but considerably worse in recessive cases with central opacification.  Glaucoma may occur in older individuals.

Systemic Features: 

None reported.

Genetics

Multiple families in Finland have been reported with inheritance patterns suggesting autosomal recessive inheritance (CNA2).  The gene has been mapped to chromosome 12 (12q21) in a region containing the KERA gene.  A Cuban family with autosomal dominant cornea plana (CDA1) also yielded linkage to 12q where the recessive gene is located.  However, this locus could be excluded in two Finnish families suggesting that at least 3 autosomal mutations may be responsible.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Correction of the hyperopia may be helpful.  Patients need to be followed and treated for glaucoma if it develops.  Outcomes of penetrating keratoplasty are not available but the procedure carries increased risk since the stroma is often thinner than normal. 
 

References
Article Title: 

The genetics of cornea plana congenita

Tahvanainen, E.; Forsius, H.; Kolehmainen, J.; Damsten, M.; Fellman, J.; de la Chapelle, A. :  The genetics of cornea plana congenita. J. Med. Genet. 33: 116-119, 1996.

PubMed ID: 
8929947

Mutations in KERA, encoding keratocan, cause cornea plana

Pellegata, N. S.; Dieguez-Lucena, J. L.; Joensuu, T.; Lau, S.; Montgomery, K. T.; Krahe, R.; Kivela, T.; Kucherlapati, R.; Forsius, H.; de la Chapelle, A. :  Mutations in KERA, encoding keratocan, cause cornea plana. Nature Genet. 25: 91-95, 2000.

PubMed ID: 
10802664

Gyrate Atrophy

Clinical Characteristics
Ocular Features: 

Gyrate atrophy is characterized by night blindness, myopia, and multiple round islands of peripheral chorioretinal degeneration which often appear in the first decade of life, sometimes as early as five years of age. Night blindness often begins in late childhood. The atrophic areas slowly progress to the posterior pole and may eventually affect central vision. Both eyes are usually symmetrically affected. All patients have myopia, some with refractive errors ranging up to -20 D. Fluorescein angiography shows hyperfluorescent at the edges of the peripheral atrophy. A zone of pigmentary changes can be seen between normal and atrophic areas.  The electroretinogram may show reduced rod and cone responses with rods affected more than cones in early phases. Dark-adapted ERG documents elevated rod thresholds.  Swollen mitochondria have been described in photoreceptors, corneal epithelium, and in the nonpigmented ciliary epithelium.  Elevated levels of ornithine are found in plasma, urine, spinal fluid and aqueous humor.  Macular edema is commonly present and posterior subcapsular cataracts requiring surgery are common.

Systemic Features: 

Mild muscle weakness may occur due to tubular aggregates in type 2 muscle fibers, which can be visualized with electron microscopy and may lead to loss of these fibers and muscle wasting. Fine, straight hairs have been observed with patches of alopecia. Slow wave background changes on EEG have been described in about one-third of patients and peripheral neuropathy is sometimes a feature.  Hearing loss has been described as well. Some newborns have a temporary elevation of plasma ammonia but once treated usually does not recur.

Genetics

Gyrate atrophy is an autosomal recessive disorder, caused by mutations in the OAT (ornithine aminotransferase) gene on chromosome 10 (10q26).  The enzyme is part of a nuclear-encoded mitochondrial matrix complex.  Many allelic variants have been found.  A large number of affected patients of Finnish origin, most of who share the common L402P mutation, have been described.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A low protein and especially an arginine-restricted diet have been shown to slow loss of function as measured by ERG and visual field changes.
 

References
Article Title: 

Nanophthalmos 2

Clinical Characteristics
Ocular Features: 

In this condition the axial length of the globe is often only 14-16 mm (normal >20 mm) resulting in extreme hyperopia of +8-25 diopters.  Corrected vision is usually 20/40 to 20/80 but 20/200 is not uncommon.  The choroid and sclera are thickened in nanophthalmos to a greater degree than seen in common mild hyperopia.  While all ocular structures are small in microphthalmia, in nanophthalmos the lens dimensions are generally normal.  In a small globe this causes ‘crowding’ of the anterior chamber angles and angle closure glaucoma is a major risk.

Folds in the choroid and retina are common.  Choroidal effusions, retinal edema and retinal detachments are not uncommon.  The retinal pigment epithelial may have mild window defects.  Hypoplasia, cysts, yellowish discoloration, and horizontal striae of the macula have been reported.  The foveal reflex is frequently absent corresponding to the lack of a normal foveal pit as revealed by OCT.  The foveal avascular zone may be small or absent.  The disks often appear crowded.  ERGs and VEPs are usually normal.   Scleral collagen is abnormal and thickened, leading to the postulation that this interferes with suprachoroidal drainage resulting in effusion and non-rhegmatogenous retinal detachments.

Systemic Features: 

No systemic disease has been consistently associated with simple nanophthalmos. Individuals with Kenny’s syndrome, Hallerman-Streiff-Francois (234100) syndrome and oculodentodigital dysplasia syndrome (164200) with nanophthalmos have been reported.

Genetics

Nanophthalmos may result from several mutations. Most cases occur sporadically but familial cases suggesting autosomal recessive inheritance (NNO2, 609549) have been reported. The mutation is a frameshift insertion, 1143C, in the MFRP gene on chromosome 11 (11q23.3) and has been found in the homozygous configuration in several families. The protein product has a domain that may be related to the Frizzled family of transmembrane  cell-cell signaling molecules responsible for regulation of growth and differentiation. In this connection, it is of interest that this gene is highly expressed in the retinal pigment epithelium.

It seems that at least two dominant mutations can also cause nanophthalmos. One (NNO3, 611897), located on chromosome 2 (2q11-q14), has been identified in a large Chinese pedigree although the molecular mutation remains unknown. Another, NNO1, (600165), has also been mapped to chromosome 11 but at 11p.  The molecular mutations also remain unknown.

Homozygous mutations in serine protease PR2258 have also been reported in several families with nanophthalmos.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Prophylactic iridotomies should be considered.
 

References
Article Title: 

Familial nanophthalmos

Cross HE, Yoder F. Familial nanophthalmos. Am J Ophthalmol. 1976 81(3):300-6.

PubMed ID: 
1258954

The nanophthalmic macula

Serrano JC, Hodgkins PR, Taylor DS, Gole GA, Kriss A. The nanophthalmic macula. Br J Ophthalmol. 1998 Mar;82(3):276-9.

PubMed ID: 
9602624

Mutations in a novel serine protease PRSS56 in families with nanophthalmos

Orr A, Dub?(c) MP, Zenteno JC, Jiang H, Asselin G, Evans SC, Caqueret A, Lakosha H, Letourneau L, Marcadier J, Matsuoka M, Macgillivray C, Nightingale M, Papillon-Cavanagh S, Perry S, Provost S, Ludman M, Guernsey DL, Samuels ME. Mutations in a novel serine protease PRSS56 in families with nanophthalmos. Mol Vis. 2011;17:1850-61.  PubMed PMID: 21850159.

PubMed ID: 
21850159

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