pigmentary retinopathy

Cystinosis

Clinical Characteristics
Ocular Features: 

Cystinosis is a clinically heterogeneous disorder that has been divided into three allelic forms based on the age of onset and the amount of kidney disease.  Since the three types are caused by mutations in the same CTNS gene they are discussed here as a single entity with emphasis on the similarities and differences.  All three cause significant corneal disease secondary to crystalline cystine deposits.

The early onset and most common form of cystinosis (219800) causes severe photophobia and even corneal erosions from accumulation of refractile cystine crystals which can be seen in the first years of life.  Accumulation of cystine in the retina leads to peripheral pigmentary changes that progress centrally and is present to some degree in all patients by age 7 years.  Mottling of the retinal pigment epithelium is the most common finding but there are often alternating areas of hyperpigmentation and depigmentation as well.  Visual fields may be markedly constricted.  Photoreceptor damage eventually leads to decreased rod and cone responses as recorded by ERG.  Visual acuity ranges from near normal to NLP.

The late-onset juvenile nephropathic (219900) form has a similar corneal profile but the pigmentary retinopathy occurs later than in the infantile disease.

The adult nonnephropathic form (219750) likewise has visible cystine crystals in the cornea.  This disorder should be considered in all healthy adults with a crystalline dystrophy of the cornea.  The pigmentary retinopathy does not occur.

Systemic Features: 

In the more common infantile form of cystinosis, accumulation of cystine leads to dysfunction in many organs.  Nephropathy, hypothyroidism, and growth retardation in the infantile type are major complications.  The kidney disease leads to a Fanconi syndrome type pattern of kidney failure.  Pancreatic insufficiency, ovarian failure, myopathy, and central nervous system signs are often seen.  Patients require renal transplantation, often in the first decade of life.  Slow eating and dysphagia are common.  Heterozygotes may have elevated levels of free cystine in leukocytes.

The later onset juvenile form of cystinosis presents with kidney failure secondary to glomerular damage instead of tubular dysfunction.  The age of diagnosis varies widely, however, anywhere from 2-26 years of age, with end-stage kidney failure occurring generally in the third decade.  Aminoaciduria is usually not present and growth is normal.

The adult-onset or benign type is also uncommon.  Patients with this non-nephropathic type (219750), of course, do not develop kidney disease but have demonstrable cystine deposits in the cornea, buffy coat, and bone marrow.  No proteinuria or amino aciduria is detectable.

Genetics

Cystinosis is an autosomal recessive disease that is found in individuals homozygous for mutations in the CTNS gene (17p13) that encodes cystinosin.  The most common mutation among Caucasians of European descent is a 57-kb deletion which sometimes includes contiguous and regulatory genes.  Other sequence variants have also been found.  High cystine levels can be demonstrated in leucocytes of heterozygotes, at least in the infantile form.   A large number of mutations, both homozygous and compound heterozygous, have been found .  The accumulation of cystine seems to result from impaired cystine transport across the lysosomal membrane and it has been suggested that the severity of disease depends on the amount of functional cystinosin produced by various mutations in the CTNS gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Topical cysteamine eye drops can dramatically reduce the number of cornea crystals and improve symptoms such as photophobia and visual acuity.  Oral administration of the same drug can be beneficial for systemic disease as well, especially if initiated before the age of two years.  It can also reduce the frequency and severity of posterior segment disease with the most benefit occurring in those who begin the drug early in life.  Improved kidney function and quality of life may be dramatic.

The chronic nature and multisystem involvement require lifelong monitoring of ocular and systemic disease.

References
Article Title: 

Nanophthalmos Plus Syndrome

Clinical Characteristics
Ocular Features: 

This is a recently described type of nanophthalmos with characteristic clinical features plus retinal degeneration and optic disc drusen.  Hyperopia is common and, like another recessive form of nanophthalmos (267760), patients have a progressive retinal dystrophy beginning with granular and mottled RPE changes and progressing to a bone spicule pattern resembling retinitis pigmentosa.  No synechiae have been reported in this syndrome however.  Macular retinoschisis and cystic changes with reduced foveal reflexes are commonly present.  The anterior chamber and angles are narrow but no reported cases have had angle closure glaucoma such as frequently occurs in other forms of nanophthalmos (267760, 609549, 600165, 611897).  Drusen of the optic nerve head can be demonstrated by ultrasound.  Scleral and choroidal thickening are usually present.  There is progressive deterioration of photoreceptors beginning with rod dysfunction and eventually involving cones as documented on ERG recordings.  Nyctalopia and visual difficulties begin in childhood and the visual field is concentrically constricted.  Visual acuity is in the range of 20/100 to 20/200.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal recessive disorder caused by mutations in the membrane frizzled-related protein coding gene MFRP (11q23) expressed in retinal tissue.  Both homozygous and compound heterozygous mutations have been described.  It seems to be allelic to another nanophthalmos condition without retinal pigmentary degeneration which is caused by different mutations in MFRP (NNO2 609549).  However, there is considerable clinical overlap of the several nanophthalmos conditions and it is possible that this is simply clinical heterogeneity within the same disease.

A syndromic form (MCOP5) of autosomal recessive microphthalmia with retinitis pigmentosa (611040) is also caused by mutations in MFRP and may be the same disorder.

For other forms of nanophthalmos see:  267760, 609549, 600165, 611897.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Angle closure glaucoma is a constant threat in some nanophthalmic conditions but has not been reported in this disorder.  Nevertheless, it may be prudent to consider prophylactic iridotomies in high risk cases.

References
Article Title: 

Kearns-Sayre Syndrome

Clinical Characteristics
Ocular Features: 

Ptosis and progressive ophthalmoplegia usually have their onset before the second decade of life.  Pigmentary retinopathy is common with a variable clinical pattern of simple salt-and-pepper pigmentation or pigmentary clumping resembling retinitis pigmentosa.

Systemic Features: 

Atrioventricular conduction defects including complete heart block, cardiomyopathy, short stature, elevated CSF protein, and ataxia are among the most frequent extraocular features seen.  Pharyngeal, facial, and skeletal muscle weakness seem to be common features.  Growth retardation, delayed sexual maturation, and mental deterioration occur in some patients. Older patients have a sensorineural hearing deficit as well.

EEG abnormalities are often present.  CT scans reveals a diffuse leukoencephalopathy as well as a variety of CNS abnormalities in the cerebellum and brain stem.  Muscle biopsies reveal 'ragged red' fibers.

This is a progressive disorder and many patients die in the third or fourth decades of life.

Genetics

Unlike many syndromes of external ophthalmoplegia with deletions in mitochondria, no nuclear DNA mutations have been associated with this disorder.  However, it is a clinically and genetically heterogeneous condition.  Exclusively maternal transmission consistent with mitochondrial disease has been observed in some familial cases.  Other familial cases suggest autosomal inheritance and in some the transmission pattern is consistent with autosomal recessive inheritance.  Many if not most cases occur sporadically.

Mitochondrial DNA defects in muscle and brain vary in size and location and even the proportion of normal to abnormal mitochondria among cells varies. This may account for some of the clinical heterogeneity.

Treatment
Treatment Options: 

Coenzyme Q(10) may decrease fatigue with improvement in eye muscle movement and a lessening in the degree of heart block.  Pacemakers may be necessary in some patients.  Exercise is recommended for patients with significant skeletal myopathy.

References
Article Title: 

Bardet-Biedl Syndromes

Clinical Characteristics
Ocular Features: 

The term Bardet-Biedl is applied to a clinically and genetically diverse group of disorders, of which at least 21 entities (BBS1-BBS21) are recognized.  This discussion is generically relevant to all of the phenotypes since the retinal dystrophy is common to all.

A progressive rod-cone dystrophy is a cardinal feature of all forms of Bardet-Biedl syndrome.  However, a subset of patients have primary cone degeneration.  In at least some forms of this syndrome, the cause seems to be a defect in the cilia that impairs the intraciliary protein transport between the inner and outer segments of the photoreceptors.  Vision loss has an early onset and usually progresses rapidly with severe loss of central and peripheral vision by the second or third decade of life.  Night blindness may be evident by 7 or 8 years of age.  The ERG is not recordable even in early childhood.  Pigmentary changes in the retina are often labeled retinitis pigmentosa but they are atypical for the usual disease.  Early changes are more characteristic of atrophy with a paucity of pigment but later the bone spicule pattern of hyperpigmentation appears.  The macula can appear atrophic and sometimes has a bull's eye pattern.  Optic atrophy and retinal arteriole narrowing may be seen.  Bardet-Biedl syndrome is clinically similar to Biemond syndrome (210350) except for iris colobomas that occur in the latter disorder.

Systemic Features: 

Obesity, mental retardation, renal disease, and hepatic fibrosis with syndactyly, brachydactyly, and post-axial polydactyly are characteristic.  The degree of mental handicap varies widely.  Diabetes mellitus is present in about one-third of patients.  Structural deformities of genitalia as well as hypogonadism and menstrual irregularities often occur as in some other disorders but the association of severe vision loss and characteristic retinal changes are diagnostically helpful.  Kidney failure secondary to cystic nephronophthisis or other renal malformations is common. Hypercholesterolemia is found in many patients.  Many patients have motor difficulties, appearing clumsy and unsteady.  Emotional lability and inappropriate outbursts can be part of these syndromes as well.

Genetics

The syndromes of Bardet-Biedl are inherited in an autosomal recessive pattern.  At least 21 mutations have been identified.  Not all cases are caused by homozygosity of the same mutation since compound heterozygosity at two loci may also cause similar phenotypes.

Laurence-Moon syndrome (245800) is considered part of the Bardet-Biedl group of diseases in this database. 

Mutations in PNPLA6 have been found in some individuals with a form of Bardet-Biedl syndrome as well as in Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome, and Trichomegaly Plus Syndrome (275400), in this database.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment exists for these syndromes but organ specific therapy may be helpful.

Studies in a mice model suggest that the neural retina may at least partially recover in type 1 following subretinal injection of viral vectors containing the wild-type bbs1 gene.

 

References
Article Title: 

Bardet-Biedl Syndrome

Suspitsin EN, Imyanitov EN. Bardet-Biedl Syndrome. Mol Syndromol. 2016 May;7(2):62-71.

PubMed ID: 
27385362

Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl Syndrome

Scheidecker S, Hull S, Perdomo Y, Studer F, Pelletier V, Muller J, Stoetzel C, Schaefer E, Defoort-Dhellemmes S, Drumare I, Holder Graham E, Hamel Christian P, Webster Andrew R, Moore Anthony T, Puech B, Dollfus Helene J. Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl Syndrome. Am J Ophthalmol. 2015 May 14. [Epub ahead of print]. 

PubMed ID: 
25982971

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes

Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94.

PubMed ID: 
25480986

Mutations in IFT172 Cause Isolated Retinal Degeneration and Bardet-Biedl Syndrome

Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C, Carpentier W, Mohand-Sayid S, den Hollander AI, Cremers FP, Leroy BP, Gai X, Sahel JA, van den Born LI, Collin RW, Zeitz C, Audo I, Pierce EA. Mutations in IFT172 Cause Isolated Retinal Degeneration and Bardet-Biedl Syndrome. Hum Mol Genet. 2014 Aug 28.  [Epub ahead of print].

PubMed ID: 
25168386

Cohen Syndrome

Clinical Characteristics
Ocular Features: 

Patients have early onset night blindness with defective dark adaptation and corresponding ERG abnormalities.  Visual fields are constricted peripherally and central visual acuity is variably reduced.  A pigmentary retinopathy is often associated with a bull’s eye maculopathy. The retinopathy is progressive as is high myopia.  The eyebrows and eyelashes are long and thick and the eyelids are highly arched and often ‘wave-shaped’.  Congenital ptosis, optic atrophy, and ectopia lentis have also been reported.

Systemic Features: 

Affected individuals have a characteristic facial dysmorphism in which ocular features play a role.  They have a low hairline, a prominent nasal root, and a short philtrum.  The tip of the nose appears bulbous. The head circumference is usually normal at birth but lags behind in growth so that older individuals appear microcephalic.  Delays in developmental milestones are noticeable in the first year of life.  Mild to moderate mental retardation is characteristic but does not progress.  Hypotonia is common early, and many individuals are short in stature.  Low white counts and frank neutropenia are often seen and some patients have frequent infections, especially of the oral mucosa and the respiratory tract.  A cheerful disposition is said to be characteristic.

Genetics

This is an autosomal recessive disorder caused by a mutation in the COH1 (VPS13B) gene on chromosome 8 (8q22-q23).  However, a variety of mutations have been reported including deletions and missense substitutions and, since these are scattered throughout the gene, complete sequencing is necessary before a negative result can be confirmed.

There is evidence of significant clinical heterogeneity between cohorts descended from different founder mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Corrective lenses for myopia can be helpful.  For patients with sufficient vision, low vision aids can be helpful.  Selected individuals may benefit from vocational and speech therapy.  Infections should be treated promptly.

References
Article Title: 

Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport

Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns JP, de la Chapelle A, Lehesjoki AE. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003 Jun;72(6):1359-69.

PubMed ID: 
12730828

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: 

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